Imidazo-pyrimidine derivatives as ligands for gaba receptors

ABSTRACT

A class of imidazo[1,2-α]pyrimidine derivatives, substituted at the 3-position by an optionally substituted five-membered or six-membered heteroaromatic ring, are selective ligands for GABA A  receptors, in particular having good affinity for the α2 and/or α3 and/or α5 subunit thereof, and are accordingly of benefit in the treatment and/or prevention of adverse conditions of the central nervous system, including anxiety, convulsions and cognitive disorders.

[0001] The present invention relates to a class of substitutedimidazo-pyrimidine derivatives and to their use in therapy. Moreparticularly, this invention is concerned with imidazo[1,2-α]pyrimidineanalogues which are substituted in the 3-position by an optionallysubstituted heteroaromatic ring. These compounds are ligands forGABA_(A) receptors and are therefore useful in the therapy ofdeleterious mental states.

[0002] Receptors for the major inhibitory neurotransmitter,gamma-aminobutyric acid (GABA), are divided into two main classes: (1)GABA_(A) receptors, which are members of the ligand-gated ion channelsuperfamily; and (2) GABA_(B) receptors, which may be members of theG-protein linked receptor superfamily. Since the first cDNAs encodingindividual GABA_(A) receptor subunits were cloned the number of knownmembers of the mammalian family has grown to include at least six asubunits, four β subunits, three γ subunits, one β subunit, one εsubunit and two ρ subunits.

[0003] Although knowledge of the diversity of the GABA_(A) receptor genefamily represents a huge step forward in our understanding of thisligand-gated ion channel, insight into the extent of subtype diversityis still at an early stage. It has been indicated that an a subunit, a βsubunit and a γ subunit constitute the minimum requirement for forming afully functional GABA_(A) receptor expressed by transiently transfectingcDNAs into cells. As indicated above, δ, ε and ρ subunits also exist,but are present only to a minor extent in GABA_(A) receptor populations.

[0004] Studies of receptor size and visualisation by electron microscopyconclude that, like other members of the ligand-gated ion channelfamily, the native GABA_(A) receptor exists in pentameric form. Theselection of at least one α, one β and one γ subunit from a repertoireof seventeen allows for the possible existence of more than 10,000pentameric subunit combinations. Moreover, this calculation overlooksthe additional permutations that would be possible if the arrangement ofsubunits around the ion channel had no constraints (i.e. there could be120 possible variants for a receptor composed of five differentsubunits).

[0005] Receptor subtype assemblies which do exist include, amongst manyothers, α1β2γ2, α2βγ1, α2β2/3γ2, α3βγ2/3, α4βδ, α5β3γ2/3, α6βγ2 andα6βδ. Subtype assemblies containing an α1 subunit are present in mostareas of the brain and are thought to account for over 40% of GABA_(A)receptors in the rat. Subtype assemblies containing α2 and α3 subunitsrespectively are thought to account for about 25% and 17% of GABA_(A)receptors in the rat. Subtype assemblies containing an α5 subunit areexpressed predominantly in the hippocampus and cortex and are thought torepresent about 4% of GABA_(A) receptors in the rat.

[0006] A characteristic property of all known GABA_(A) receptors is thepresence of a number of modulatory sites, one of which is thebenzodiazepine (BZ) binding site. The BZ binding site is the mostexplored of the GABA_(A) receptor modulatory sites, and is the sitethrough which anxiolytic drugs such as diazepam and temazepam exerttheir effect. Before the cloning of the GABA_(A) receptor gene family,the benzodiazepine binding site was historically subdivided into twosubtypes, BZ1 and BZ2, on the basis of radioligand binding studies. TheBZ1 subtype has been shown to be pharmacologically equivalent to aGABA_(A) receptor comprising the α1 subunit in combination with a βsubunit and γ2. This is the most abundant GABA_(A) receptor subtype, andis believed to represent almost half of all GABA_(A) receptors in thebrain.

[0007] Two other major populations are the α2βγ2 and α3βγ2/3 subtypes.Together these constitute approximately a further 35% of the totalGABA_(A) receptor repertoire. Pharmacologically this combination appearsto be equivalent to the BZ2 subtype as defined previously by radioligandbinding, although the BZ2 subtype may also include certain α5-containingsubtype assemblies. The physiological role of these subtypes hashitherto been unclear because no sufficiently selective agonists orantagonists were known.

[0008] It is now believed that agents acting as BZ agonists at α1βγ2,α2βγ2 or α3βγ2 subtypes will possess desirable anxiolytic properties.Compounds which are modulators of the benzodiazepine binding site of theGABA_(A) receptor by acting as BZ agonists are referred to hereinafteras “GABA_(A) receptor agonists”. The α1-selective GABA_(A) receptoragonists alpidem and zolpidem are clinically prescribed as hypnoticagents, suggesting that at least some of the sedation associated withknown anxiolytic drugs which act at the BZ1 binding site is mediatedthrough GABA_(A) receptors containing the α1 subunit. Accordingly, it isconsidered that GABA_(A) receptor agonists which interact morefavourably with the α2 and/or α3 subunit than with α1 will be effectivein the treatment of anxiety with a reduced propensity to cause sedation.Moreover, agents which are inverse agonists of the α5 subunit are likelyto be beneficial in enhancing cognition, for example in subjectssuffering from dementing conditions such as Alzheimer's disease. Also,agents which are antagonists or inverse agonists at α1 might be employedto reverse sedation or hypnosis caused by α1 agonists.

[0009] The compounds of the present invention, being selective ligandsfor GABA_(A) receptors, are therefore of use in the treatment and/orprevention of a variety of disorders of the central nervous system. Suchdisorders include anxiety disorders, such as panic disorder with orwithout agoraphobia, agoraphobia without history of panic disorder,animal and other phobias including social phobias, obsessive-compulsivedisorder, stress disorders including post-traumatic and acute stressdisorder, and generalized or substance-induced anxiety disorder;neuroses; convulsions; migraine; depressive or bipolar disorders, forexample single-episode or recurrent major depressive disorder, dysthymicdisorder, bipolar I and bipolar II manic disorders, and cyclothymicdisorder; psychotic disorders including schizophrenia; neurodegenerationarising from cerebral ischemia; attention deficit hyperactivitydisorder; speech disorders, including stuttering; and disorders ofcircadian rhythm, e.g. in subjects suffering from the effects of jet lagor shift work.

[0010] Further disorders for which selective ligands for GABA_(A)receptors may be of benefit include pain and nociception; emesis,including acute, delayed and anticipatory emesis, in particular emesisinduced by chemotherapy or radiation, as well as motion sickness, andpost-operative nausea and vomiting; eating disorders including anorexianervosa and bulimia nervosa; premenstrual syndrome; muscle spasm orspasticity, e.g. in paraplegic patients; hearing disorders, includingtinnitus and age-related hearing impairment; urinary incontinence; andthe effects of substance abuse or dependency, including alcoholwithdrawal. Selective ligands for GABA_(A) receptors may be beneficialin enhancing cognition, for example in subjects suffering from dementingconditions such as Alzheimer's disease; and may also be effective aspre-medication prior to anaesthesia or minor procedures such asendoscopy, including gastric endoscopy.

[0011] In addition, the compounds in accordance with the presentinvention may be useful as radioligands in assays for detectingcompounds capable of binding to the human GABA_(A) receptor.

[0012] The present invention provides a class of imidazo-pyrimidinederivatives which possess desirable binding properties at variousGABA_(A) receptor subtypes. The compounds in accordance with the presentinvention have good affinity as ligands for the α2 and/or α3 and/or α5subunit of the human GABA_(A) receptor. The compounds of this inventionmay interact more favourably with the α2 and/or α3 subunit than with theα1 subunit; and/or may interact more favourably with the α5 subunit thanwith the α1 subunit.

[0013] The compounds of the present invention are GABA_(A) receptorsubtype ligands having a binding affinity (K_(i)) for the α2 and/or α3and/or α5 subunit, as measured in the assay described hereinbelow, of200 nM or less, typically of 100 nM or less, and ideally of 20 nM orless. The compounds in accordance with this invention may possess atleast a 2-fold, suitably at least a 5-fold, and advantageously at leasta 10-fold, selective affinity for the α2 and/or α3 and/or α5 subunitrelative to the α1 subunit. However, compounds which are not selectivein terms of their binding affinity for the α2 and/or α3 and/or α5subunit relative to the α1 subunit are also encompassed within the scopeof the present invention; such compounds will desirably exhibitfunctional selectivity in terms of zero or weak (positive or negative)efficacy at the α1 subunit and (i) a full or partial agonist profile atthe α2 and/or α3 subunit, and/or (ii) an inverse agonist profile at theα5 subunit.

[0014] The present invention provides a compound of formula I, or a saltor prodrug thereof:

[0015] wherein

[0016] Z represents an optionally substituted five-memberedheteroaromatic ring selected from furan, thiophene, pyrrole, oxazole,thiazole, isoxazole, isothiazole, imidazole, pyrazole, oxadiazole,thiadiazole, triazole and tetrazole; or

[0017] Z represents an optionally substituted six-memberedheteroaromatic ring selected from pyridine, pyrazine, pyrimidine andpyridazine;

[0018] R¹ represents hydrogen, hydrocarbon, a heterocyclic group,halogen, cyano, trifluoromethyl, nitro, —OR^(a), —SR^(a), —SOR^(a),—SO²R^(a), —SO₂NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)COR^(b),—NR^(a)CO₂R^(b), —COR^(a), —CO₂R^(a), —CONR^(a)R^(b) or —CR^(a)═NOR^(b);and

[0019] R^(a) and R^(b) independently represent hydrogen, hydrocarbon ora heterocyclic group.

[0020] Where Z in the compounds of formula I above represents afive-membered heteroaromatic ring, this ring may be optionallysubstituted by one or, where possible, two substituents. As will beappreciated, where Z represents an oxadiazole, thiadiazole or tetrazolering, only one substituent will be possible; otherwise, one or twooptional substituents may be accommodated around the five-memberedheteroaromatic ring Z.

[0021] Where Z in the compounds of formula I above represents asix-membered heteroaromatic ring, this ring may be optionallysubstituted by one or more substituents, typically by one or twosubstituents.

[0022] Suitably, the group Z is unsubstituted or monosubstituted.

[0023] Examples of optional substituents on the five-membered orsix-membered heteroaromatic ring as specified for Z include halogen,cyano, trifluoromethyl, C₁₋₆ alkyl, halo(C₁₋₆)alkyl, dihalo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₃₋₇ cycloalkyl, C₃₋₇heterocycloalkyl, benzyl-tetrahydropyridinyl, C₁₋₆ alkoxy,methyltriazolyl(C₁₋₆)alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl, C₂₋₆alkylcarbonyl, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, C₂₋₆alkylcarbonylamino, phenyl, (C₁₋₆)alkyl-phenyl, halophenyl,dihalophenyl, trihalophenyl, (fluoro)(methyl)phenyl, cyanophenyl,(cyano)(fluoro)phenyl, (cyano)(difluoro)phenyl, difluoromethyl-phenyl,trifluoromethyl-phenyl, (methyl)(trifluoromethyl)phenyl,(halo)(trifluoromethyl)phenyl, nitrophenyl, methoxyphenyl,(halo)(methoxy)phenyl, trifluoromethoxy-phenyl,(halo)(trifluoromethoxy)phenyl, methylenedioxy-phenyl,(C₂₋₆)alkylcarbonyl-phenyl, trifluorothio-phenyl,(C₁₋₆)alkylsulphonyl-phenyl, di(C₁₋₆)alkylaminocarbonyl-phenyl,di(C₁₋₆)alkylaminosulphonyl-phenyl, (halo)(morpholinylmethyl)phenyl,(halo)(pyridinyl)phenyl, imidazolyl-phenyl, thiadiazolyl-phenyl,methylthiadiazolyl-phenyl, (halo)(triazolyl)phenyl,methyltetrazolyl-phenyl and optionally substituted heteroaryl, theoptional substituents on the heteroaryl moiety being typically selectedfrom oxy, halogen, cyano and C₁₋₆ alkyl.

[0024] Examples of typical substituents on the five-membered orsix-membered ring as specified for Z include halogen, cyano,trifluoromethyl, C₁₋₆ alkyl, halo(C₁₋₆)alkyl, C₁₋₆ alkoxy(C₁₋₆)alkyl,C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy,methyltriazolyl(C₁₋₆)alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl, amino,C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, C₂₋₆ alkylcarbonylamino, phenyl,fluorophenyl, chlorophenyl, cyanophenyl, (fluoro)(cyano)phenyl,nitrophenyl, methoxyphenyl, thiadiazolyl-phenyl,methylthiadiazolyl-phenyl, methyltetrazolyl-phenyl and optionallysubstituted heteroaryl, the optional substituents on the heteroarylmoiety being typically selected from oxy, halogen, cyano and C₁₋₆ alkyl.

[0025] Examples of suitable substituents on the five-membered orsix-membered heteroaromatic ring as specified for Z include halogen,cyano, trifluoromethyl, C₁₋₆ alkyl, halo(C₁₋₆)alkyl, C₃₋₇ cycloalkyl,C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, amino, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, cyanophenyl, methoxyphenyl andheteroaryl.

[0026] For use in medicine, the salts of the compounds of formula I willbe pharmaceutically acceptable salts. Other salts may, however, beuseful in the preparation of the compounds according to the invention orof their pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid. Furthermore, where the compounds ofthe invention carry an acidic moiety, suitable pharmaceuticallyacceptable salts thereof may include alkali metal salts, e.g. sodium orpotassium salts; alkaline earth metal salts, e.g. calcium or magnesiumsalts; and salts formed with suitable organic ligands, e.g. quaternaryammonium salts.

[0027] The term “hydrocarbon” as used herein includes straight-chained,branched and cyclic groups containing up to 18 carbon atoms, suitably upto 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitablehydrocarbon groups include C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, indanyl, aryl andaryl(C₁₋₆)alkyl.

[0028] The expression “a heterocyclic group” as used herein includescyclic groups containing up to 18 carbon atoms and at least oneheteroatom preferably selected from oxygen, nitrogen and sulphur. Theheterocyclic group suitably contains up to 15 carbon atoms andconveniently up to 12 carbon atoms, and is preferably linked throughcarbon. Examples of suitable heterocyclic groups include C₃₋₇heterocycloalkyl, C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl, heteroaryl andheteroaryl(C₁₋₆)alkyl groups.

[0029] Suitable alkyl groups include straight-chained and branched alkylgroups containing from 1 to 6 carbon atoms. Typical examples includemethyl and ethyl groups, and straight-chained or branched propyl, butyland pentyl groups. Particular alkyl groups are methyl, ethyl, n-propyl,isopropyl, isobutyl, tert-butyl and 2,2-dimethylpropyl. Derivedexpressions such as “C₁₋₆ alkoxy”, “C₁₋₆ alkylamino” and “C₁₋₆alkylsulphonyl” are to be construed accordingly.

[0030] Suitable alkenyl groups include straight-chained and branchedalkenyl groups containing from 2 to 6 carbon atoms. Typical examplesinclude vinyl, allyl and dimethylallyl groups.

[0031] Suitable alkynyl groups include straight-chained and branchedalkynyl groups containing from 2 to 6 carbon atoms. Typical examplesinclude ethynyl and propargyl groups.

[0032] Suitable cycloalkyl groups include groups containing from 3 to 7carbon atoms. Particular cycloalkyl groups are cyclopropyl andcyclohexyl.

[0033] Typical examples of C₃₋₇ cycloalkyl(C₁₋₆)alkyl groups includecyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl.

[0034] Particular indanyl groups include indan-1-yl and indan-2-yl.

[0035] Particular aryl groups include phenyl and naphthyl, preferablyphenyl.

[0036] Particular aryl(C₁₋₆)alkyl groups include benzyl, phenylethyl,phenylpropyl and naphthylmethyl.

[0037] Suitable heterocycloalkyl groups include azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinylgroups.

[0038] Suitable heteroaryl groups include pyridinyl, quinolinyl,isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, benzofuryl,dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl,indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolylgroups.

[0039] The expression “heteroaryl(C₁₋₆)alkyl” as used herein includesfurylmethyl, furylethyl, thienylmethyl, thienylethyl, oxazolylmethyl,oxazolylethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl,imidazolylethyl, oxadiazolylmethyl, oxadiazolylethyl,thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl,tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl,pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl andisoquinolinylmethyl.

[0040] The hydrocarbon and heterocyclic groups may in turn be optionallysubstituted by one or more groups selected from C₁₋₆ alkyl, adamantyl,phenyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ aminoalkyl, trifluoromethyl,hydroxy, C₁₋₆ alkoxy, aryloxy, keto, C₁₋₃ alkylenedioxy, nitro, cyano,carboxy, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, C₂₋₆alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, C₂₋₆ alkylcarbonyl,arylcarbonyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsulphonyl,arylsulphonyl, —NR^(v)R^(w), —NR^(v)COR^(w), —NR^(v)CO₂R^(w),—NR^(v)SO₂R^(w), —CH₂NR^(v)SO₂R^(w), —NHCONR^(v)R^(w), —CONR^(v)R^(w),—SO₂NR^(v)R^(w) and —CH₂SO₂NR^(v)R^(w), in which R^(v) and R^(w)independently represent hydrogen, C₁₋₆ alkyl, aryl or aryl(C₁₋₆)alkyl.

[0041] The term “halogen” as used herein includes fluorine, chlorine,bromine and iodine, especially fluoro or chloro.

[0042] The present invention includes within its scope prodrugs of thecompounds of formula I above. In general, such prodrugs will befunctional derivatives of the compounds of formula I which are readilyconvertible in vivo into the required compound of formula I.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

[0043] Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

[0044] Where the group Z represents an optionally substitutedfive-membered heteroaromatic ring, this is suitably a thiophene,thiazole or thiadiazole ring, either of which may be optionallysubstituted by one or, where possible, two substituents.

[0045] Where the group Z represents an optionally substitutedsix-membered heteroaromatic ring, this is suitably a pyridinyl orpyrimidinyl ring, either of which may be optionally substituted by oneor more substituents, typically by one or two substituents. In oneembodiment, Z represents monosubstituted pyridinyl. In anotherembodiment, Z represents monosubstituted pyrimidinyl.

[0046] Illustrative examples of optional substituents on the group Zinclude fluoro, chloro, bromo, iodo, cyano, trifluoromethyl, methyl,isopropyl, tert-butyl, chloromethyl, fluoropropyl (especially2-fluoroprop-2-yl), difluoroethyl (especially 1,1-difluoroethyl),hydroxypropyl (especially 2-hydroxyprop-2-yl), methoxymethyl,cyclopentyl, pyrrolidinyl, morpholinyl, benzyl-tetrahydropyridinyl,methoxy, ethoxy, isopropoxy, tert-butoxy, methyltriazolyl-methoxy,methylthio, ethylthio, methanesulphonyl, acetyl, tert-butylamino,dimethylamino, acetylamino, phenyl, methylphenyl, isopropylphenyl,tert-butylphenyl, fluorophenyl, chlorophenyl, bromophenyl,difluorophenyl, dichlorophenyl, dibromophenyl, (chloro)(fluoro)phenyl,trifluorophenyl, trichlorophenyl, (fluoro)(methyl)phenyl, cyanophenyl,(cyano)(fluoro)phenyl, (cyano)(difluoro)phenyl, difluoromethyl-phenyl,trifluoromethyl-phenyl, (methyl)(trifluoromethyl)phenyl,(chloro)(trifluoromethyl)phenyl, nitrophenyl, methoxyphenyl,(fluoro)(methoxy)phenyl, trifluoromethoxy-phenyl,(fluoro)(trifluoromethoxy)phenyl, methylenedioxy-phenyl, acetylphenyl,trifluorothio-phenyl, methanesulphonyl-phenyl, ethanesulphonyl-phenyl,dimethylaminocarbonyl-phenyl, dimethylaminosulphonyl-phenyl,(fluoro)(morpholinylmethyl)phenyl, (fluoro)(pyridinyl)phenyl,imidazolyl-phenyl, thiadiazolyl-phenyl, methylthiadiazolyl-phenyl,(fluoro)(triazolyl)phenyl, methyltetrazolyl-phenyl, pyridinyl,oxypyridinyl, fluoropyridinyl, chloropyridinyl, cyanopyridinyl,methylpyridinyl, dimethyl-pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, furyl, thienyl, cyanothienyl, pyrrolyl, pyrazolyl, oxazolyl,thiazolyl, isothiazolyl, imidazolyl, methylimidazolyl and triazolyl.

[0047] Suitable examples of optional substituents on the group Z includefluoro, chloro, bromo, iodo, cyano, trifluoromethyl, methyl, tert-butyl,chloromethyl, methoxymethyl, cyclopentyl, pyrrolidinyl, morpholinyl,methoxy, ethoxy, isopropoxy, tert-butoxy, methyltriazolyl-methoxy,methylthio, ethylthio, methanesulphonyl, tert-butylamino, dimethylamino,acetylamino, phenyl, fluorophenyl, chlorophenyl, cyanophenyl,(cyano)(fluoro)phenyl, nitrophenyl, methoxyphenyl, thiadiazolyl-phenyl,methylthiadiazolyl-phenyl, methyltetrazolyl-phenyl, pyridinyl,oxypyridinyl, chloropyridinyl, cyanopyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, furyl, thienyl, cyanothienyl, pyrrolyl, pyrazolyl, oxazolyl,thiazolyl, isothiazolyl, imidazolyl, methylimidazolyl and triazolyl.

[0048] Typical examples of optional substituents on the group Z includehalogen, cyano, trifluoromethyl, C₁₋₆ alkyl, halo(C₁₋₆)alkyl, C₃₋₇cycloalkyl, C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy, cyanophenyl, thienyl andpyridinyl. Examples of specific substituents on the group Z includechloro, bromo, cyano, trifluoromethyl, methyl, chloromethyl,cyclopentyl, pyrrolidinyl (especially pyrrolidin-1-yl), methoxy,cyanophenyl (especially 2-cyanophenyl), thienyl (especially thien-2-yl)and pyridinyl (especially pyridin-3-yl).

[0049] One particular substituent on the group Z is cyanophenyl,especially 2-cyanophenyl.

[0050] Another particular substituent on the group Z is fluorophenyl.

[0051] A preferred substituent on the group Z is difluorophenyl.

[0052] Illustrative values of Z include pyridinyl, bromopyridinyl,cyanopyridinyl, trifluoromethyl-pyridinyl, methylpyridinyl,cyclopentylpyridinyl, pyrrolidinyl-pyridinyl, methoxypyridinyl,cyanophenyl-pyridinyl, chloropyrimidinyl, cyanophenyl-pyrimidinyl,pyridinyl-thienyl, thiazolyl, pyridinyl-thiazolyl,chloromethyl-thiadiazolyl and thienyl-thiadiazolyl.

[0053] Specific values of Z include pyridin-2-yl, 3-bromopyridin-2-yl,5-cyanopyridin-2-yl, 5-trifluoromethylpyridin-2-yl,6-trifluoromethylpyridin-2-yl, 5-methylpyridin-2-yl,6-methylpyridin-2-yl, 6-cyclopentylpyridin-2-yl,6-(pyrrolidin-1-yl)pyridin-2-yl, 6-methoxypyridin-2-yl,6-(2-cyanophenyl)pyridin-2-yl, 2-(2-cyanophenyl)pyridin-4-yl,2-chloropyrimidin-4-yl, 2-(2-cyanophenyl)pyrimidin-4-yl,4-(pyridin-3-yl)thien-2-yl, 2-(pyridin-3-yl)thien-4-yl, thiazol-2-yl,4-(pyridin-3-yl)thiazol-2-yl, 3-chloromethyl-[1,2,4]thiazol-5-yl and3-(thien-2-yl)-[1,2,4]thiazol-5-yl.

[0054] A favoured value of Z is fluorophenyl-pyrimidinyl.

[0055] A preferred value of Z is difluorophenyl-pyrimidinyl.

[0056] Typically, R¹ represents hydrogen, hydrocarbon, a heterocyclicgroup, halogen, cyano, trifluoromethyl, —OR^(a), —COR^(a), —CO₂R^(a) or—CR^(a)═NOR^(b).

[0057] Typical values of R^(a) include hydrogen and C₁₋₆ alkyl.Suitably, R^(a) represents hydrogen or methyl.

[0058] Typical values of R^(b) include hydrogen, C₁₋₆ alkyl,hydroxy(C₁₋₆)alkyl and di(C₁₋₆)alkylamino(C₁₋₆)alkyl. Suitably, R^(b)represents hydrogen, methyl, ethyl, hydroxyethyl or dimethylaminoethyl.Particular values of R^(b) include hydrogen, hydroxyethyl anddimethylaminoethyl, especially hydrogen or dimethylaminoethyl.

[0059] Representative values of R¹ include hydrogen, C₁₋₆ alkyl,halo(C₁₋₆)alkyl, dihalo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, C₁₋₆alkoxy(C₁₋₆)alkyl, di(C₁₋₆)alkoxy(C₁₋₆)alkyl, C₃₋₇ cycloalkyl,heteroaryl, C₁₋₆ alkyl-heteroaryl, heteroaryl(C₁₋₆)alkyl, halogen,cyano, trifluoromethyl, C₁₋₆ alkoxy, formyl, C₂₋₆ alkylcarbonyl, C₂₋₆alkoxycarbonyl and —CR^(a)═NOR^(b), in which R^(a) and R^(b) are asdefined above. In addition, R¹ may represent cyano(C₁₋₆)alkyl.

[0060] Individual values of R¹ include C₁₋₆ alkyl, halo(C₁₋₆)alkyl,cyano(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, di(C₁₋₆)alkoxy(C₁₋₆)alkyl,heteroaryl(C₁₋₆)alkyl, trifluoromethyl and C₂₋₆ alkylcarbonyl.

[0061] Itemised values of R¹ include hydrogen, methyl, fluoromethyl,difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl,hydroxyethyl (especially 1-hydroxyethyl), fluoroethyl (especially1-fluoroethyl), difluoroethyl (especially 1,1-difluoroethyl),dimethoxyethyl (especially 1,1-dimethoxyethyl), isopropyl, hydroxypropyl(especially 2-hydroxyprop-2-yl), fluoropropyl (especially2-fluoroprop-2-yl), tert-butyl, cyclopropyl, cyclobutyl, pyridinyl,furyl, thienyl, oxazolyl, methylthiazolyl, methyloxadiazolyl,imidazolylmethyl, triazolylmethyl, chloro, cyano, trifluoromethyl,methoxy, formyl, acetyl, methoxycarbonyl and —CR²═NOR³, in which R²represents hydrogen or methyl, and R³ represents hydrogen, hydroxyethylor dimethylaminoethyl. In addition, R¹ may represent cyanopropyl(especially 2-cyanoprop-2-yl).

[0062] Representative values of R¹ include dimethoxyethyl (especially1,1-dimethoxyethyl), cyanopropyl (especially 2-cyanoprop-2-yl),hydroxypropyl (especially 2-hydroxyprop-2-yl), fluoropropyl (especially2-fluoroprop-2-yl), tert-butyl, triazolylmethyl, trifluoromethyl andacetyl.

[0063] A favoured value of R¹ is 2-hydroxyprop-2-yl.

[0064] A particular value of R¹ is trifluoromethyl.

[0065] Suitably, R² is hydrogen.

[0066] Suitably, R³ represents hydrogen or dimethylaminoethyl,especially hydrogen.

[0067] A particular sub-class of compounds according to the invention isrepresented by the compounds of formula IA, and salts and prodrugsthereof:

[0068] wherein

[0069] Z is as defined above;

[0070] R¹¹ represents hydrogen, C₁₋₆ alkyl, cyano(C₁₋₆)alkyl,halo(C₁₋₆)alkyl, dihalo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, C₁₋₆alkoxy(C₁₋₆)alkyl, di(C₁₋₆)alkoxy(C₁₋₆)alkyl, C₃₋₇ cycloalkyl,heteroaryl, C₁₋₆ alkyl-heteroaryl, heteroaryl(C₁₋₆)alkyl, halogen,cyano, trifluoromethyl, C₁₋₆ alkoxy, formyl, C₂₋₆ alkylcarbonyl, C₂₋₆alkoxycarbonyl or —CR⁴═NOR⁵;

[0071] R⁴ represents hydrogen or C₁₋₆ alkyl; and

[0072] R⁵ represents hydrogen, C₁₋₆ alkyl, hydroxy(C₁₋₆)alkyl ordi(C₁₋₆)alkylamino(C₁₋₆)alkyl.

[0073] The present invention also provides a compound of formula IA asdepicted above, or a salt thereof or a prodrug thereof, wherein

[0074] R¹¹ represents hydrogen, C₁₋₆ alkyl, halo(C₁₋₆)alkyl,dihalo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy(C₁₋₆)alkyl,di(C₁₋₆)alkoxy(C₁₋₆)alkyl, C₃₋₇ cycloalkyl, heteroaryl, C₁₋₆alkyl-heteroaryl, heteroaryl(C₁₋₆)alkyl, halogen, cyano,trifluoromethyl, C₁₋₆ alkoxy, formyl, C₂₋₆ alkylcarbonyl, C₂₋₆alkoxycarbonyl or —CR⁴═NOR⁵; and

[0075] Z, R⁴ and R⁵ are as defined above.

[0076] Suitably, R⁴ represents hydrogen or methyl, especially hydrogen.

[0077] Suitably, R⁵ represents hydrogen, methyl, ethyl, hydroxyethyl ordimethylaminoethyl. Particular values of R⁵ include hydrogen,hydroxyethyl and dimethylaminoethyl. Typically, R⁵ represents hydrogenor dimethylaminoethyl, especially hydrogen.

[0078] Where R¹¹ represents heteroaryl, this group is suitablypyridinyl, furyl, thienyl or oxazolyl.

[0079] Where R¹¹ represents C₁₋₆ alkyl-heteroaryl, this group issuitably methylthiazolyl (e.g. 2-methylthiazol-5-yl) ormethyloxadiazolyl (e.g. 3-methyl-[1,2,4]oxadiazol-5-yl).

[0080] Where R¹¹ represents heteroaryl(C₁₋₆)alkyl, this group issuitably imidazolylmethyl or triazolylmethyl.

[0081] Itemised values of R¹¹ include hydrogen, methyl, fluoromethyl,difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl,hydroxyethyl (especially 1-hydroxyethyl), fluoroethyl (especially1-fluoroethyl), difluoroethyl (especially 1,1-difluoroethyl),dimethoxyethyl (especially 1,1-dimethoxyethyl), isopropyl, hydroxypropyl(especially 2-hydroxyprop-2-yl), fluoropropyl (especially2-fluoroprop-2-yl), tert-butyl, cyclopropyl, cyclobutyl, pyridinyl,furyl, thienyl, oxazolyl, methylthiazolyl, methyloxadiazolyl,imidazolylmethyl, triazolylmethyl, chloro, cyano, trifluoromethyl,methoxy, formyl, acetyl, methoxycarbonyl and —CR²═NOR³, in which R² andR³ are as defined above. In addition, R¹¹ may represent cyanopropyl(especially 2-cyanoprop-2-yl).

[0082] Representative values of R¹¹ include dimethoxyethyl (especially1,1-dimethoxyethyl), cyanopropyl (especially 2-cyanoprop-2-yl),hydroxypropyl (especially 2-hydroxyprop-2-yl), fluoropropyl (especially2-fluoroprop-2-yl), tert-butyl, triazolylmethyl, trifluoromethyl andacetyl.

[0083] A favoured value of R¹¹ is 2-hydroxyprop-2-yl.

[0084] A particular value of R¹¹ is trifluoromethyl.

[0085] One representative subset of the compounds of formula IA above isrepresented by the compounds of formula IIA, and salts and prodrugsthereof:

[0086] wherein

[0087] X represents CH and Y represents N; or

[0088] X represents N and Y represents CH or N;

[0089] R⁶ represents hydrogen, halogen, cyano, trifluoromethyl, C₁₋₆alkyl, halo(C₁₋₆)alkyl, dihalo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, C₁₋₆alkoxy(C₁₋₆)alkyl, C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl,benzyl-tetrahydropyridinyl, C₁₋₆ alkoxy, methyltriazolyl(C₁₋₆)alkoxy,C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl, C₂₋₆ alkylcarbonyl, amino, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, C₂₋₆ alkylcarbonylamino, phenyl,(C₁₋₆)alkyl-phenyl, halophenyl, dihalophenyl, trihalophenyl,(fluoro)(methyl)phenyl, cyanophenyl, (cyano)(fluoro)phenyl,(cyano)(difluoro)phenyl, difluoromethyl-phenyl, trifluoromethyl-phenyl,(methyl)(trifluoromethyl)phenyl, (halo)(trifluoromethyl)phenyl,nitrophenyl, methoxyphenyl, (halo)(methoxy)phenyl,trifluoromethoxy-phenyl, (halo)(trifluoromethoxy)phenyl,methylenedioxy-phenyl, (C₂₋₆)alkylcarbonyl-phenyl, trifluorothio-phenyl,(C₁₋₆)alkylsulphonyl-phenyl, di(C₁₋₆)alkylaminocarbonyl-phenyl,di(C₁₋₆)alkylaminosulphonyl-phenyl, (halo)(morpholinylmethyl)phenyl,(halo)(pyridinyl)phenyl, imidazolyl-phenyl, thiadiazolyl-phenyl,methylthiadiazolyl-phenyl, (halo)(triazolyl)phenyl,methyltetrazolyl-phenyl or optionally substituted heteroaryl, theoptional substituents on the heteroaryl moiety being selected from oxy,halogen, cyano and C₁₋₆ alkyl; and

[0090] R¹¹ is as defined above.

[0091] The present invention also provides a compound of formula IIA asdepicted above, or a salt thereof or a prodrug thereof, wherein

[0092] R⁶ represents hydrogen, halogen, cyano, trifluoromethyl, C₁₋₆alkyl, halo(C₁₋₆)alkyl, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₃₋₇ cycloalkyl, C₃₋₇heterocycloalkyl, C₁₋₆ alkoxy, methyltriazolyl(C₁₋₆)alkoxy, C₁₋₆alkylthio, C₁₋₆ alkylsulphonyl, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, C₂₋₆ alkylcarbonylamino, phenyl, fluorophenyl,chlorophenyl, cyanophenyl, (fluoro)(cyano)phenyl, nitrophenyl,methoxyphenyl, thiadiazolyl-phenyl, methylthiadiazolyl-phenyl,methyltetrazolyl-phenyl or optionally substituted heteroaryl, theoptional substituents on the heteroaryl moiety being selected from oxy,halogen, cyano and C₁₋₆ alkyl; and

[0093] X, Y and R¹¹ are as defined above.

[0094] The present invention further provides a compound of formula IIAas depicted above, or a salt thereof or a prodrug thereof, wherein

[0095] R⁶ represents hydrogen, halogen, cyano, trifluoromethyl, C₁₋₆alkyl, C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, C₁₋₆ alkoxy orcyanophenyl; and

[0096] X, Y and R¹¹ are as defined above.

[0097] Illustrative values of R⁶ include hydrogen, fluoro, chloro,bromo, iodo, cyano, trifluoromethyl, methyl, isopropyl, tert-butyl,chloromethyl, fluoropropyl (especially 2-fluoroprop-2-yl), difluoroethyl(especially 1,1-difluoroethyl), hydroxypropyl (especially2-hydroxyprop-2-yl), methoxymethyl, cyclopentyl, pyrrolidinyl,morpholinyl, benzyl-tetrahydropyridinyl, methoxy, ethoxy, isopropoxy,tert-butoxy, methyltriazolyl-methoxy, methylthio, ethylthio,methanesulphonyl, acetyl, tert-butylamino, dimethylamino, acetylamino,phenyl, methylphenyl, isopropylphenyl, tert-butylphenyl, fluorophenyl,chlorophenyl, bromophenyl, difluorophenyl, dichlorophenyl,dibromophenyl, (chloro)(fluoro)phenyl, trifluorophenyl, trichlorophenyl,(fluoro)(methyl)phenyl, cyanophenyl, (cyano)(fluoro)phenyl,(cyano)(difluoro)phenyl, difluoromethyl-phenyl, trifluoromethyl-phenyl,(methyl)(trifluoromethyl)phenyl, (chloro)(trifluoromethyl)phenyl,nitrophenyl, methoxyphenyl, (fluoro)(methoxy)phenyl,trifluoromethoxy-phenyl, (fluoro)(trifluoromethoxy)phenyl,methylenedioxy-phenyl, acetylphenyl, trifluorothio-phenyl,methanesulphonyl-phenyl, ethanesulphonyl-phenyl,dimethylaminocarbonyl-phenyl, dimethylaminosulphonyl-phenyl,(fluoro)(morpholinylmethyl)phenyl, (fluoro)(pyridinyl)phenyl,imidazolyl-phenyl, thiadiazolyl-phenyl, methylthiadiazolyl-phenyl,(fluoro)(triazolyl)phenyl, methyltetrazolyl-phenyl, pyridinyl,oxypyridinyl, fluoropyridinyl, chloropyridinyl, cyanopyridinyl,methylpyridinyl, dimethyl-pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, furyl, thienyl, cyanothienyl, pyrrolyl, pyrazolyl, oxazolyl,thiazolyl, isothiazolyl, imidazolyl, methylimidazolyl and triazolyl.

[0098] Suitable values of R⁶ include hydrogen, fluoro, chloro, bromo,iodo, cyano, trifluoromethyl, methyl, tert-butyl, chloromethyl,methoxymethyl, cyclopentyl, pyrrolidinyl, morpholinyl, methoxy, ethoxy,isopropoxy, tert-butoxy, methyltriazolyl-methoxy, methylthio, ethylthio,methanesulphonyl, tert-butylamino, dimethylamino, acetylamino, phenyl,fluorophenyl, chlorophenyl, cyanophenyl, (fluoro)(cyano)phenyl,nitrophenyl, methoxyphenyl, thiadiazolyl-phenyl,methylthiadiazolyl-phenyl, methyltetrazolyl-phenyl, pyridinyl,oxypyridinyl, chloropyridinyl, cyanopyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, furyl, thienyl, cyanothienyl, pyrrolyl, pyrazolyl, oxazolyl,thiazolyl, isothiazolyl, imidazolyl, methylimidazolyl and triazolyl.

[0099] Typical values of R⁶ include hydrogen, chloro, bromo, cyano,trifluoromethyl, methyl, cyclopentyl, pyrrolidinyl (especiallypyrrolidin-1-yl), methoxy and cyanophenyl (especially 2-cyanophenyl).

[0100] A favoured value of R⁶ is fluorophenyl.

[0101] A preferred value of R⁶ is difluorophenyl.

[0102] An illustrative subset of the compounds of formula IIA above isrepresented by the compounds of formula IIB, and salts and prodrugsthereof:

[0103] wherein X, Y and R¹¹ are as defined above.

[0104] Another illustrative subset of the compounds of formula IIA aboveis represented by the compounds of formula IIC, and salts and prodrugsthereof:

[0105] wherein

[0106] R¹⁶ represents hydrogen, fluoro or cyano; and

[0107] X, Y and R¹¹ are as defined above.

[0108] In a favoured embodiment, R¹⁶ represents hydrogen.

[0109] In another embodiment, R¹⁶ represents cyano.

[0110] In a preferred embodiment, R¹⁶ represents fluoro.

[0111] In one embodiment of the compounds of formula IIA, IIB and IIC, Xis CH and Y is N.

[0112] In another embodiment of the compounds of formula IIA, IIB andIIC, X is N and Y is CH.

[0113] In a further embodiment of the compounds of formula IIA, IIB andIIC, X and Y are both N.

[0114] Specific compounds within the scope of the present inventioninclude:

[0115]3-(6-bromopyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0116]2-[6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]-benzonitrile;

[0117]2-[4-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]-benzonitrile;

[0118]3-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0119]3-(2-chloropyrimidin-4-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0120] 3-(thiazol-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0121] 6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)nicotinonitrile;

[0122] 3-(pyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0123]3-[6-(pyrrolidin-1-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0124]7-trifluoromethyl-3-(6-trifluoromethylpyridin-2-yl)imidazo[1,2-α]pyrimidine;

[0125]3-(6-methylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0126]3-(6-methoxypyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0127]3-(6-cyclopentylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0128]3-(5-methylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0129]7-trifluoromethyl-3-(5-trifluoromethylpyridin-2-yl)imidazo[1,2-α]pyrimidine;

[0130]2-[4-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyrimidin-2-yl]-benzonitrile;

[0131]3-[3-(thien-2-yl)-[1,2,4]thiadiazol-5-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0132]3-[4-(pyridin-3-yl)thien-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0133]3-[5-(pyridin-3-yl)thien-3-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0134]3-[4-(pyridin-3-yl)thiazol-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0135]2-{6-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile;

[0136]5-fluoro-2-{6-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile;

[0137]3-{6-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}thiophene-2-carbonitrile;

[0138]4-fluoro-2-{6-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile;

[0139]3-(6-bromopyridin-2-yl)-7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine;

[0140]2-{6-[7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile;

[0141]2-{6-[7-(1-cyano-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile;

[0142]2-[6-(7-tert-butylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]-5-fluorobenzonitrile;

[0143]4-fluoro-2-[6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]benzonitrile;

[0144]3-(2-fluoropyridin-5-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0145]3-(2-phenylpyridin-5-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0146]3-[2-(4-fluorophenyl)pyridin-5-yl)]-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0147]3-[2-(1H-pyrrol-1-yl)pyridin-5-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0148]3-(2-chloropyrimidin-4-yl)-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidine;

[0149]5-fluoro-2-{4-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]-pyrimidin-2-yl}benzonitrile;

[0150]2-[3-(2-(pyridin-3-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol;

[0151]2-{4-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}thiophene-3-carbonitrile;

[0152]5-fluoro-2-{4-[7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}benzonitrile;

[0153]2-[3-(2-trifluoromethylpyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol;

[0154]2-[3-(2-(thiazol-2-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol;

[0155]2-[3-(2-(imidazol-1-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol;

[0156]2-[3-(2-(pyridin-4-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol

[0157]2-[3-(2-(furan-2-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol;

[0158]2-[3-(2-(furan-3-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol;

[0159]2-{3-[2-(1-oxypyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol;

[0160]3-[6-(1H-imidazol-1-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0161]3-[6-(morpholin-4-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0162]3-(6-phenylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0163]6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,3′-bipyridine;

[0164]N-[6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]acetamide;

[0165]N-(tert-butyl)-6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-ylamine;

[0166]3-[6-(1H-[1,2,4]triazol-1-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0167]3-[6-(isothiazol-4-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0168]3-(6-isopropoxypyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0169]3-(6-ethoxypyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0170]6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,2′-bipyridine;

[0171]6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,4′-bipyridine;

[0172]3-(6-methoxymethylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0173]3-[6-(thien-3-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;

[0174]7-(1,1-dimethoxyethyl)-3-[2-(pyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine;

[0175]2-{3-[2-(3-nitrophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol;

[0176]2-{3-[2-(3-fluorophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol;

[0177]1-[3-(2-(pyridin-4-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]ethanone;

[0178]6-[7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-α]pyrimidinyl-3-yl]-2,3′-bipyridine;

[0179]2-[6-(7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]benzonitrile;

[0180]6′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,2′-bipyridinyl-3-carbonitrile;

[0181]6′-[7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]-2,2′-bipyridinyl-3-carbonitrile;

[0182] the compounds whose structures are depicted in the accompanyingTables as Examples 68 to 109;

[0183]2-{3-[2-(2,4-difluorophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol;

[0184]2-{3-[2-(3,4-difluorophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol;

[0185]2-{3-[2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol;

[0186]2-{3-[2-(1,1-difluoroethyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol;

[0187]1-{4-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}ethanone;

[0188]2-{3-[2-(1-hydroxy-1-methylethyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol;

[0189]2-{3-[2-(1-fluoro-1-methylethyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol;

[0190]2-[3-(2-isopropylpyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol;

[0191] the compounds whose structures are depicted in the accompanyingTables as Examples 118 to 200;

[0192] and salts and prodrugs thereof.

[0193] Also provided by the present invention is a method for thetreatment and/or prevention of anxiety which comprises administering toa patient in need of such treatment an effective amount of a compound offormula I as defined above or a pharmaceutically acceptable salt thereofor a prodrug thereof.

[0194] Further provided by the present invention is a method for thetreatment and/or prevention of convulsions (e.g. in a patient sufferingfrom epilepsy or a related disorder) which comprises administering to apatient in need of such treatment an effective amount of a compound offormula I as defined above or a pharmaceutically acceptable salt thereofor a prodrug thereof.

[0195] The binding affinity (K_(i)) of the compounds according to thepresent invention for the α3 subunit of the human GABA_(A) receptor isconveniently as measured in the assay described hereinbelow. The α3subunit binding affinity (K_(i)) of the anxiolytic compounds of theinvention is ideally 50 nM or less, preferably 10 nM or less, and morepreferably 5 nM or less.

[0196] The anxiolytic compounds according to the present invention willideally elicit at least a 40%, preferably at least a 50%, and morepreferably at least a 60%, potentiation of the GABA EC₂₀ response instably transfected recombinant cell lines expressing the α3 subunit ofthe human GABA_(A) receptor. Moreover, the compounds of the inventionwill ideally elicit at most a 30%, preferably at most a 20%, and morepreferably at most a 10%, potentiation of the GABA EC₂₀ response instably transfected recombinant cell lines expressing the α1 subunit ofthe human GABA_(A) receptor.

[0197] The potentiation of the GABA EC₂₀ response in stably transfectedcell lines expressing the α3 and α1 subunits of the human GABA_(A)receptor can conveniently be measured by procedures analogous to theprotocol described in Wafford et al., Mol. Pharmacol., 1996, 50,670-678. The procedure will suitably be carried out utilising culturesof stably transfected eukaryotic cells, typically of stably transfectedmouse Ltk⁻ fibroblast cells.

[0198] The compounds according to the present invention may exhibitanxiolytic activity, as may be demonstrated by a positive response inthe elevated plus maze and conditioned suppression of drinking tests(cf. Dawson et al., Psychopharmacology, 1995, 121, 109-117). Moreover,the compounds of the invention are likely to be substantiallynon-sedating, as may be confirmed by an appropriate result obtained fromthe response sensitivity (chain-pulling) test (cf. Bayley et al., J.Psychopharmacol., 1996, 10, 206-213).

[0199] The compounds according to the present invention may also exhibitanticonvulsant activity. This can be demonstrated by the ability toblock pentylenetetrazole-induced seizures in rats and mice, following aprotocol analogous to that described by Bristow et al. in J. Pharmacol.Exp. Ther., 1996, 279, 492-501.

[0200] In another aspect, the present invention provides a method forthe treatment and/or prevention of cognitive disorders, includingdementing conditions such as Alzheimer's disease, which comprisesadministering to a patient in need of such treatment an effective amountof a compound of formula I as defined above or a pharmaceuticallyacceptable salt thereof.

[0201] Cognition enhancement can be shown by testing the compounds inthe Morris watermaze as reported by McNamara and Skelton, Psychobiology,1993, 21, 101-108. Further details of relevant methodology are describedin WO 96/25948.

[0202] Cognitive disorders for which the compounds of the presentinvention may be of benefit include delirium, dementia, amnesticdisorders, and cognition deficits, including age-related memorydeficits, due to traumatic injury, stroke, Parkinson's disease and DownSyndrome. Any of these conditions may be attributable to substance abuseor withdrawal. Examples of dementia include dementia of the Alzheimer'stype with early or late onset, and vascular dementia, any of which maybe uncomplicated or accompanied by delirium, delusions or depressedmood; and dementia due to HIV disease, head trauma, Parkinson's diseaseor Creutzfeld-Jakob disease.

[0203] In order to elicit their behavioural effects, the compounds ofthe invention will ideally be brain-penetrant; in other words, thesecompounds will be capable of crossing the so-called “blood-brainbarrier”. Preferably, the compounds of the invention will be capable ofexerting their beneficial therapeutic action following administration bythe oral route.

[0204] The invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, auto-injector devices orsuppositories; for oral, parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules. This solid preformulation composition is thensubdivided into unit dosage forms of the type described above containingfrom 0.1 to about 500 mg of the active ingredient of the presentinvention. Typical unit dosage forms contain from 1 to 100 mg, forexample 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

[0205] The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

[0206] In the treatment of neurological disorders, a suitable dosagelevel is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100mg/kg per day, and especially about 0.05 to 5 mg/kg per day. Thecompounds may be administered on a regimen of 1 to 4 times per day.

[0207] The compounds in accordance with the present invention may beprepared by a process which comprises reacting a compound of formula IIIwith a compound of formula IV:

 L¹-Z   (IV)

[0208] wherein Z and R¹ are as defined above, L¹ represents a suitableleaving group, and M¹ represents a boronic acid moiety —B(OH)₂ or acyclic ester thereof formed with an organic diol, e.g. pinacol,1,3-propanediol or neopentyl glycol, or M¹ represents —Sn(Alk)₃ in whichAlk represents a C₁₋₆ alkyl group, typically n-butyl; in the presence ofa transition metal catalyst.

[0209] The leaving group L¹ is typically a halogen atom, e.g. bromo orchloro.

[0210] The transition metal catalyst of use in the reaction betweencompounds III and IV is suitablytetrakis(triphenylphosphine)-palladium(0). The reaction is convenientlycarried out at an elevated temperature in a solvent such astetrahydrofuran, 1,4-dioxane or N,N-dimethylacetamide, typically in thepresence of potassium phosphate, cesium carbonate or copper(I) iodide.

[0211] In an alternative procedure, the compounds according to thepresent invention may be prepared by a process which comprises reactinga compound of formula V with a compound of formula VI:

 M¹-Z   (V)

[0212] wherein Z, R¹, L¹ and M¹ are as defined above; in the presence ofa transition metal catalyst; under conditions analogous to thosedescribed above for the reaction between compounds III and IV.

[0213] In another procedure, the compounds according to the presentinvention wherein Z represents a thiazol-2-yl moiety substituted at the4-position by a substituent R⁷, in which R⁷ represents any allowablesubstituent on the group Z (in particular wherein R⁷ representspyridin-3-yl), may be prepared by a process which comprises reacting acompound of formula VII with a compound of formula VIII:

[0214] wherein R¹ and R⁷ are as defined above, and Hal represents ahalogen atom, e.g. bromo.

[0215] The reaction between compounds VII and VIII is convenientlyeffected at an elevated temperature in a solvent such asN,N-dimethylformamide.

[0216] Where M¹ in the intermediates of formula III above represents—Sn(Alk)₃ in which Alk is n-butyl, this compound may be prepared byreacting a compound of formula V as defined above with tributyltinchloride.

[0217] The reaction is conveniently effected by stirring compound V withisopropylmagnesium chloride in a solvent such as tetrahydrofuran, withsubsequent addition of tributyltin chloride.

[0218] Where L¹ in the intermediates of formula V above representsbromo, this compound may be prepared by bromination of the correspondingcompound of formula IX:

[0219] wherein R¹ is as defined above; typically by treatment withbromine in methanol, in the presence of sodium acetate and optionallyalso potassium bromide.

[0220] The intermediates of formula IX may be prepared by reactingchloroacetaldehyde or bromoacetaldehyde, or an acetal derivativethereof, e.g. the dimethyl or diethyl acetal thereof, with the requisitecompound of formula X:

[0221] wherein R¹ is as defined above.

[0222] Where chloroacetaldehyde or bromoacetaldehyde is utilised as oneof the reactants, the reaction is conveniently carried out by heatingthe reactants under basic conditions in a suitable solvent, e.g. sodiummethoxide or sodium hydrogencarbonate in a lower alkanol such asmethanol and/or ethanol at the reflux temperature of the solvent. Wherean acetal derivative of chloroacetaldehyde or bromoacetaldehyde, e.g.the dimethyl or diethyl acetal thereof, is utilised as one of thereactants, the reaction is conveniently effected by heating thereactants under acidic conditions in a suitable solvent, e.g. aqueoushydrobromic acid in a lower alkanol such as methanol or ethanol,typically at the reflux temperature of the solvent.

[0223] The intermediates of formula IX may also be prepared by reactinga compound of formula XI or XII with the compound of formula XIII, orwith an acid addition salt of the latter compound, e.g. the hemisulfatesalt:

[0224] wherein R¹ is as defined above, and Alk¹ represents C₁₋₆ alkyl.

[0225] Typical values of Alk¹ include methyl and ethyl.

[0226] The reaction is conveniently effected by heating the reactantsunder basic conditions in a suitable solvent, e.g. a lower alkoxide suchas sodium methoxide or ethoxide in a lower alkanol such as methanol orethanol, typically at the reflux temperature of the solvent.

[0227] The intermediates of formula VII above may be prepared from theappropriate compound of formula XIV:

[0228] wherein R¹ and Alk¹ are as defined above; by treatment withammonia, typically in aqueous ethanol, followed by treatment of theresulting amide derivative with Lawesson's reagent[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide],typically in refluxing toluene.

[0229] The intermediates of formula XIV may be prepared by reacting acompound of formula X as defined above with N,N-dimethylformamidedimethyl acetal, followed by treatment of the product thereby obtainedwith ethyl bromoacetate.

[0230] Both steps of this transformation may conveniently beaccomplished by heating under reflux in toluene.

[0231] In another procedure, the compounds according to the presentinvention wherein R¹ represents an aryl or heteroaryl moiety may beprepared by a process which comprises reacting a compound of formula XVwith a compound of formula XVI:

R^(1a)-M¹   (XV)

[0232] wherein Z and M¹ are as defined above, R^(1a) represents an arylor heteroaryl moiety, and L² represents a suitable leaving group; in thepresence of a transition metal catalyst.

[0233] The leaving group L² is typically a halogen atom, e.g. chloro.

[0234] The transition metal catalyst of use in the reaction betweencompounds XV and XVI is suitablytetrakis(triphenylphosphine)-palladium(0), in which case the reaction isconveniently effected at an elevated temperature in a solvent such asN,N-dimethylacetamide, typically in the presence of potassium phosphateor in the presence of lithium chloride and copper(I) iodide.Alternatively, the transition metal catalyst may suitably betris(dibenzylideneacetone)palladium(0), in which case the reaction isconveniently effected at an elevated temperature in a solvent such as1,4-dioxane, typically in the presence of tri-tert-butylphosphine andcesium carbonate.

[0235] Where L² in the compounds of formula XVI above represents ahalogen atom, these compounds correspond to compounds of formula I asdefined above wherein R¹ represents halogen, and they may therefore beprepared by any of the methods described above for the preparation ofthe compounds according to the invention.

[0236] In a further procedure, the compounds according to the inventionmay be prepared by a process which comprises reacting a compound offormula IV as defined above with a compound of formula IX as definedabove in the presence of a transition metal catalyst.

[0237] The transition metal catalyst of use in the reaction betweencompounds IV and IX is suitablytetrakis(triphenylphosphine)-palladium(0), in which case the reaction isconveniently effected at an elevated temperature in a solvent such as1,4-dioxane, typically in the presence of cesium carbonate.

[0238] The compound of formula XIII above is commercially available fromthe Sigma-Aldrich Company Ltd., Dorset, United Kingdom.

[0239] Where they are not commercially available, the starting materialsof formula IV, VI, VIII, X, XI, XII and XV may be prepared by methodsanalogous to those described in the accompanying Examples, or bystandard methods well known from the art.

[0240] It will be understood that any compound of formula I initiallyobtained from any of the above processes may, where appropriate,subsequently be elaborated into a further compound of formula I bytechniques known from the art. For example, a compound of formula Iinitially obtained wherein the moiety Z is substituted by a halogenatom, e.g. bromo, may be converted into the corresponding compoundwherein the moiety Z is substituted by an aryl or heteroaryl group, e.g.2-cyanophenyl or pyridin-3-yl, by treatment with the requisite aryl orheteroaryl boronic acid or cyclic ester thereof formed with an organicdiol, e.g. 2-cyanophenylboronic acid or pyridine-3-boronicacid-1,3-propanediol cyclic ester, in the presence of a transition metalcatalyst such as tetrakis(triphenylphosphine)palladium(0), in which casethe reaction is conveniently effected at an elevated temperature in asolvent such as N,N-dimethylacetamide, aqueous 1,4-dioxane or aqueoustetrahydrofuran, typically in the presence of potassium phosphate,sodium carbonate or cesium carbonate; or by treatment with theappropriate stannyl reagent, e.g. 2-tributylstannylbenzonitrile, in thepresence of a transition metal catalyst such asdichloro[1,1′-bis(diphenylphosphino)ferrocene]-palladium(II), in whichcase the reaction is conveniently effected at a elevated temperature ina solvent such as N,N-dimethylacetamide, typically in the presence oflithium chloride and copper(I) chloride; or by treatment with theappropriate stannyl reagent in the presence of a transition metalcatalyst such as tetrakis(triphenylphosphine)-palladium(0), in whichcase the reaction is conveniently accomplished at an elevatedtemperature in a solvent such as tetrahydrofuran or 1,4-dioxane,typically in the presence of copper(I) iodide; or, where the moiety Z inthe desired compound of formula I is substituted by imidazol-1-yl,simply by treatment with imidazole in the presence of a strong base suchas lithium hexamethyldisilazide (LiHMDS). A compound of formula Iwherein the moiety Z is substituted by pyridinyl may be converted intothe corresponding compound wherein Z is substituted by N-oxypyridinyl bytreatment with meta-chloroperbenzoic acid. A compound of formula Iwherein Z is substituted by a halogen atom, e.g. iodo, may be converted,by treatment with isopropylmagnesium chloride, into a Grignard reagentwhich may be reacted with an aldehyde such as acetaldehyde to afford asecondary alcohol, e.g. the 1-hydroxyethyl derivative; and this compoundmay in turn be treated with an oxidising agent, e.g. Dess-Martinperiodinane, to afford the corresponding compound of formula I wherein Zis substituted by acetyl. The resulting acetyl derivative may beconverted, by treatment with methylmagnesium chloride, into thecorresponding compound wherein Z is substituted by 2-hydroxyprop-2-yl;and this compound may in turn be treated with (diethylamino)sulfurtrifluoride (DAST) to afford the corresponding compound of formula Iwherein Z is substituted by 2-fluoroprop-2-yl. A compound of formula Iwherein R¹ represents —C(O-Alk¹)₂R^(a) initially obtained, wherein Alk¹is as defined above, may be converted into the corresponding compound offormula I wherein R¹ represents —COR^(a) by hydrolysis with a mineralacid, typically aqueous hydrochloric acid. A compound wherein R¹represents formyl may be reduced with sodium triacetoxyborohydride tothe corresponding compound wherein R¹ represents hydroxymethyl. Acompound of formula I wherein R¹ represents hydroxymethyl may beoxidised to the corresponding compound of formula I wherein R¹represents formyl by treatment with manganese dioxide. The formylderivative thereby obtained may be condensed with a hydroxylaminederivative of formula H₂N—OR^(b) to provide a compound of formula Iwherein R¹ represents —CH═NOR^(b). Furthermore, a compound of formula Iwherein R¹ represents —CH═NOH may be treated with triethylamine in thepresence of 1,1′-carbonyldiimidazole to afford a corresponding compoundof formula I wherein R¹ represents cyano. Alternatively, the compound offormula I wherein R¹ represents formyl may be reacted with a Grignardreagent of formula R^(a)MgBr to afford a compound of formula I whereinR¹ represents —CH(OH)R^(a), and this compound may in turn be oxidisedusing manganese dioxide to the corresponding compound of formula Iwherein R¹ represents —COR^(a). The latter compound may then becondensed with a hydroxylamine derivative of formula H₂N—OR^(b) toprovide a compound of formula I wherein R¹ represents —CR^(a)═NOR^(b). Acompound of formula I wherein R¹ represents —CH(OH)R^(a) may beconverted into the corresponding compound of formula I wherein R¹represents —CHFR^(a) by treatment with DAST. Similarly, a compound offormula I wherein R¹ represents —COR^(a) may be converted into thecorresponding compound of formula I wherein R¹ represents —CF₂R^(a) bytreatment with DAST. A compound of formula I wherein R¹ represents aminomay be converted into the corresponding compound of formula I wherein R¹represents chloro by diazotisation, using sodium nitrite, followed bytreatment with copper(I) chloride. A compound of formula I wherein R¹represents —COCH₃ may be treated with thioacetamide in the presence ofpyridinium tribromide to furnish the corresponding compound of formula Iwherein R¹ represents 2-methylthiazol-5-yl. Moreover, a compound offormula I wherein R¹ is formyl may be treated with(p-tolylsulfonyl)methyl isocyanide (TosMIC) in the presence of potassiumcarbonate to afford the corresponding compound of formula I wherein R¹represents oxazol-5-yl. A compound of formula I wherein R¹ representshydroxymethyl may be treated with carbon tetrabromide andtriphenylphosphine to afford the corresponding compound of formula Iwherein R¹ represents bromomethyl, which may then be reacted (typicallyin situ) with the sodium salt of imidazole or 1H-[1,2,4]triazole toprovide a compound of formula I wherein R¹ representsimidazol-1-ylmethyl or [1,2,4]triazol-1-ylmethyl respectively; or withthe sodium salt of 1H-[1,2,3]triazole to provide a mixture of compoundsof formula I wherein R¹ represents [1,2,3]triazol-1-ylmethyl and[1,2,3]triazol-2-ylmethyl; or with morpholine to provide a compound offormula I wherein R¹ represents morpholin-4-ylmethyl.

[0241] Where a mixture of products is obtained from any of the processesdescribed above for the preparation of compounds according to theinvention, the desired product can be separated therefrom at anappropriate stage by conventional methods such as preparative HPLC; orcolumn chromatography utilising, for example, silica and/or alumina inconjunction with an appropriate solvent system.

[0242] Where the above-described processes for the preparation of thecompounds according to the invention give rise to mixtures ofstereoisomers, these isomers may be separated by conventional techniquessuch as preparative chromatography. The novel compounds may be preparedin racemic form, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The novel compounds may, forexample, be resolved into their component enantiomers by standardtechniques such as preparative HPLC, or the formation of diastereomericpairs by salt formation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The novel compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

[0243] During any of the above synthetic sequences it may be necessaryand/or desirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

[0244] The following Examples illustrate the preparation of compoundsaccording to the invention.

[0245] The compounds in accordance with this invention potently inhibitthe binding of [³H]-flumazenil to the benzodiazepine binding site ofhuman GABA_(A) receptors containing the α2 and/or α3 and/or α5 subunitstably expressed in Ltk⁻ cells.

[0246] Reagents

[0247] Phosphate buffered saline (PBS).

[0248] Assay buffer: 10 mM KH₂PO₄, 100 mM KCl, pH 7.4 at roomtemperature.

[0249] [³H-Flumazenil (18 nM for α1β3γ2 cells; 18 nM for α2β3γ2 cells;10 nM for α3β3γ2 cells; 10 nM for α5β3γ2 cells) in assay buffer.

[0250] Flumazenil 100 μM in assay buffer.

[0251] Cells resuspended in assay buffer (1 tray to 10 ml).

Harvesting Cells

[0252] Supernatant is removed from cells. PBS (approximately 20 ml) isadded. The cells are scraped and placed in a 50 ml centrifuge tube. Theprocedure is repeated with a further 10 ml of PBS to ensure that most ofthe cells are removed. The cells are pelleted by centrifuging for 20 minat 3000 rpm in a benchtop centrifuge, and then frozen if desired. Thepellets are resuspended in 10 ml of buffer per tray (25 cm×25 cm) ofcells.

Assay

[0253] Can be carried out in deep 96-well plates or in tubes; Each tubecontains:

[0254] 300 μl of assay buffer.

[0255] 50 μl of [³H]-flumazenil (final concentration for α1β3γ2: 1.8 nM;for α2β3γ2: 1.8 nM; for α3β3γ2: 1.0 nM; for α5β3γ2: 1.0 nM).

[0256] 50 μl of buffer or solvent carrier (e.g. 10% DMSO) if compoundsare dissolved in 10% DMSO (total); test compound or flunitrazepam (todetermine non-specific binding), 10 μM final concentration.

[0257] 100 μl of cells.

[0258] Assays are incubated for 1 hour at 40° C., then filtered usingeither a Tomtec or Brandel cell harvester onto GF/B filters followed by3×3 ml washes with ice cold assay buffer. Filters are dried and countedby liquid scintillation counting. Expected values for total binding are3000-4000 dpm for total counts and less than 200 dpm for non-specificbinding if using liquid scintillation counting, or 1500-2000 dpm fortotal counts and less than 200 dpm for non-specific binding if countingwith meltilex solid scintillant. Binding parameters are determined bynon-linear least squares regression analysis, from which the inhibitionconstant K_(i) can be calculated for each test compound.

[0259] The compounds of the accompanying Examples were tested in theabove assay, and all were found to possess a K_(i) value fordisplacement of [³H]-flumazenil from the α2 and/or α3 and/or α5 subunitof the human GABA_(A) receptor of 100 nM or less.

EXAMPLE 13-(6-Bromopyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0260] A mixture of 2-amino-4-(trifluoromethyl)pyrimidine (preparedaccording to Zanatta et al. in J. Heterocyclic Chem., 1997, 34(2),509-513) (500 mg, 3.1 mmol) and bromoacetaldehyde diethyl acetal (1.38ml, 9.2 mmol) in ethanol (10 ml) was treated with hydrobromic acid (0.5ml of a 48% aqueous solution) and then heated at 70° C. for 12 h. Thereaction was cooled to ambient temperature then pre-adsorbed ontosilica. Purification by chromatography on silica eluting withdichloromethane (containing 1% conc. ammonia) on a gradient of methanol(1-5%) afforded 7-trifluoromethylimidazo[1,2-α]pyrimidine (500 mg, 87%)as a cream-coloured solid: δ_(H) (400 MHz, CDCl₃) 7.22 (1H, d, J 7),7.74 (1H, d, J 1), 8.03 (1H, d, J 1), 8.67 (1H, d, J 7).

[0261] 7-Trifluoromethylimidazo[1,2-α]pyrimidine (20. g, 10.7 mmol) andsodium acetate (1.1 mg, 13.4 mmol) were dissolved in methanol (30 ml)which had been saturated with potassium bromide and this mixture wascooled to −10° C. before dropwise addition of bromine (1.86 mg, 11.7mmol) over 5 min. On complete addition the mixture was quenched byaddition of 1M sodium sulfite solution (2 ml) and the solvent removed invacuo. The residue was treated with water (100 ml) and saturated sodiumhydrogencarbonate solution (100 ml) and extracted with ethyl acetate(3×100 ml). The organics were combined then washed with brine (100 ml),dried over anhydrous sodium sulfate and evaporated to give an off-whitesolid. This solid was purified by silica gel chromatography eluting withdichloromethane and 1% conc. ammonia on a gradient of methanol (1-2%) togive 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.98 g) as awhite solid: δ_(H) (400 MHz, CDCl₃) 7.35 (1H, d, J 7), 8.02 (1H, s),8.62 (1H, d, J 7).

[0262] To a cooled (−78° C.) solution of3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.0 g, 3.78 mmol) intetrahydrofuran (20 ml) was added isopropylmagnesium chloride (2.08 mlof a 2M solution in tetrahydrofuran, 4.16 mmol). After stirring for 5min tributyltin chloride (1.2 ml, 4.42 mmol) was added and the reactionstirred for 10 min at −78° C. then allowed to warm to ambienttemperature to give a solution of3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine intetrahydrofuran (ca. 0.15M): m/z (ES⁺) 474, 476, 478 (M⁺+H).

[0263] To the degassed solution of3-tributylstannyl-7-trifluoromethyl-imidazo[1,2-α]pyrimidine was added2,6-dibromopyridine (1.8 g, 7.5 mmol) andtetrakis(triphenylphosphine)palladium(0) (218 mg, 0.18 mmol) and themixture heated at reflux for 3 h. The crude reaction was adsorbed ontosilica and purified by chromatography on silica gel eluting withisohexane on a gradient of ethyl acetate (20-60%) to give a yellowsolid. Crystallisation from ethyl acetate/isohexane afforded3-(6-bromopyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (702mg) as a white solid: δ_(H) (400 MHz, DMSO) 7.64 (1H, d, J 9), 7.83 (1H,d, J 8), 7.93 (1H, dd, J 9 and 9), 8.20 (1H, d, J 9), 8.92 (1H, s),10.18 (1H, d, J 9); m/z (ES⁺) 343, 345 (M⁺+H).

EXAMPLE 22-[6-(7-Trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]-benzonitrile

[0264] To a degassed solution of3-(6-bromopyridin-2-yl)-7-trifluoromethyl-imidazo[1,2-α]pyrimidine (200mg, 0.58 mmol), 2-cyanophenylboronic acid (172 mg, 1.16 mmol) andpotassium phosphate (370 mg, 1.75 mmol) in N,N-dimethylacetamide (4 ml)was added tetrakis(triphenylphosphine)paladium(0) (33.8 mg, 29.2 μmol)and the reaction heated at 80° C. for 18 h. After cooling to ambienttemperature the reaction was poured onto a cartridge of strongcation-exchange resin and non-basic impurities removed by elution withmethanol. The product was then eluted with a 2M solution of ammonia inmethanol and evaporated to give an orange oil. This residue was purifiedby silica gel chromatography eluting with isohexane on a gradient ofethyl acetate (20-60%) to give a solid. Crystallisation from ethylacetate-dichloromethane gave2-[6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]benzonitrile(26 mg) as a white solid: δ_(H) (400 MHz, CDCl₃) 7.38 (1H, d, J 7),7.61(2H, m), 7.78 (2H, m), 7.91 (2H, m), 7.99 (1H, dd, J 9 and 9), 8.58 (1H,s), 10.62 (1H, d, J 9); m/z (ES⁺) 366 (M⁺+H).

EXAMPLE 32-[4-(7-Trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]-benzonitrile

[0265] A suspension of 2,4-dichloropyridine hydrochloride (preparedaccording to Effenberger et al. in Chem. Ber., 1992, 125, 1131) (1.24 g,6.75 mmol), 2-cyanophenylboronic acid (0.97 g, 0.98 mmol) and potassiumcarbonate (2.84 g, 20.5 mmol) in tetrahydrofuran (23 ml) and water (11ml) was degassed with nitrogen for 15 min.Tetrakis(triphenylphosphine)-palladium(0) (382 mg, 0.3 mmol) was thenadded and the mixture heated at reflux for 3 h then cooled to ambienttemperature. The tetrahydrofuran layer was removed and the aqueous layerextracted with ethyl acetate. The organics were combined, dried overmagnesium sulfate, filtered and adsorbed onto silica. Purification bychromatography on silica gel eluting with isohexane on a gradient ofethyl acetate (10-50%) gave an oil. Trituration with diethyl etherafforded 2-(4-chloropyridin-2-yl)benzonitrile (122 mg) as a white solid:δ_(H) (400 MHz, CDCl₃) 7.39 (1H, dd, J 5.3 and 1.8), 7.53-7.57 (1H, m),7.69-7.73 (1H, m), 7.76-7.84 (3H, m), 8.68 (1H, d, J 4.7); m/z (ES⁺)215, 217 (M⁺+H).

[0266] 2-(4-Chloropyridin-2-yl)benzonitrile (65 mg, 0.3 mmol) wascoupled with 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine(0.6 mmol) as described in Example 1 to give2-[4-(7-trifluoromethyl-imidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]benzonitrile(15 mg) as a white solid: δ_(H) (400 MHz, DMSO) 7.62 (1H, d, J 7.0),7.69 (1H, m), 7.88 (1H, m), 7.93 (1H, dd, J 5 and 2), 8.04 (2H, m), 8.27(1H, d, J 1), 8.60 (1H, s), 8.92 (1H, dd, J 5 and 1), 9.60 (1H, d, J 8);m/z (ES⁺) 366 (M⁺+H).

EXAMPLE 43-(3-Chloromethyl-[1,2,4]thiadiazol-5-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0267] 5-Chloro-3-chloromethyl-[1,2,4]thiadiazole (360 mg, 2.13 mmol)was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol)by the method of Example 1 to afford3-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine(115 mg) as a yellow solid: δ_(H) (400 MHz, DMSO) 5.08 (2H, s), 7.94(1H, d, J 7), 9.12 (1H, s), 10.03 (1H, d, J 7); m/z (ES⁺) 320 (M⁺+H).

EXAMPLE 53-(2-Chloropyrimidin-4-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0268] 2,4-Dichloropyrimidine (317 mg, 2.13 mmol) was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol)by the method of Example 1 to give3-(2-chloropyrimidin-4-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine(167 mg) as a white solid: δ_(H) (400 MHz, DMSO) 7.91 (1H, d, J 7), 8.25(1H, d, J 5), 8.83 (1H, d, J 5), 9.17 (1H, s), 10.22 (1H, d, J 7); m/z(ES⁺) 300, 302 (M⁺+H).

EXAMPLE 6 3-(Thiazol-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0269] 2-Bromothiazole (341 μl, 3.78 mmol) was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.8 mmol)by the method of Example 1 to give3-(thiazol-2-yl)-7-trifluoromethyl-imidazo[1,2-α]pyrimidine (162 mg) asan off-white solid: δ_(H) (400 MHz, CDCl₃) 7.40 (2H, dd, J 4 and 3),7.93 (1H, d, J 3), 8.48 (1H, s), 10.22 (1H, d, J 8); m/z (ES⁺) 271(M⁺+H).

EXAMPLE 76-(7-Trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)nicotinonitrile

[0270] 6-Chloronicotinonitrile (295 mg, 2.13 mmol) was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol)by the method of Example 1 to give6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)nicotinonitrile (142mg) as a white solid: δ_(H) (400 MHz, DMSO) 7.79 (1H, d, J 7), 8.35 (1H,m), 8.43 (1H, m), 9.06 (1H, s), 9.14 (1H, s), 10.41 (1H, d, J 7); m/z(ES⁺) 290 (M⁺+H).

EXAMPLE 8 3-(Pyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0271] 2-Chloropyridine (361 μl, 3.78 mmol) was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.89 mmol)by the method of Example 1 to give3-(pyridin-2-yl)-7-trifluoromethyl-imidazo[1,2-α]pyrimidine (134 mg) asa white solid: δ_(H) (400 MHz, CDCl₃) 7.24-7.30 (1H, m), 7.33 (1H, d, J7.0), 7.82-7.84 (2H, m), 8.51 (1H, s), 8.68-8.70 (1H, m), 10.54 (1H, d,J 7.0); m/z (ES⁺) 265 (M⁺+H).

EXAMPLE 93-[6-(Pyrrolidin-1-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0272] 2-Bromo-6-(pyrrolidin-1-yl)pyridine (481 mg, 2.1 mmol) (preparedby the method of T. Sammakia et al., J. Org. Chem., 1999, 64(13),4652-4664) was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol)by the method of Example 1 to give3-[6-(pyrrolidin-1-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine(125 mg) as a white solid: δ_(H) (360 MHz, DMSO) 2.02 (4H, t, J 6.5),3.51 (4H, bs), 6.43 (1H, d, J 8.4), 7.27 (1H, d, J 7.7), 7.63 (1H, t, J7.9), 7.71 (1H, d, J 7.4), 8.72 (1H, s), 10.51 (1H, d, J 7.4); m/z (ES⁺)334 (M⁺+H).

EXAMPLE 107-Trifluoromethyl-3-(6-trifluoromethylpyridin-2-yl)imidazo[1,2-α]pyrimidine

[0273] 2-Chloro-6-trifluoromethylpyridine (385 mg, 2.1 mmol) was coupledto 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4mmol) by the method of Example 1 to give7-trifluoromethyl-3-(6-trifluoromethyl-pyridin-2-yl)imidazo[1,2-α]pyrimidine(65 mg) as a white solid: δ_(H) (360 MHz, DMSO) 7.89 (2H, d, J 7.4),8.27 (1H, t, J 7.9), 8.46 (1H, d, J 7.4), 9.01 (1H, s), 10.26 (1H, d, J7.4); m/z (ES⁺) 333 (M⁺+H).

EXAMPLE 113-(6-Methylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0274] 2-Bromo-6-methylpyridine (367 mg, 2.1 mmol) was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol)by the method of Example 1 to give3-(6-methylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (142mg) as a white solid: δ_(H) (400 MHz, DMSO) 2.62 (3H, s), 7.26 (1H, d, J7.4), 7.70 (1H, d, J 7.4), 7.86 (1H, t, J 7.8), 7.94 (1H, s), 8.83 (1H,s), 10.55 (1H, d, J 7.8); m/z (ES⁺) 279 (M⁺+H).

EXAMPLE 123-(6-Methoxypyridin-2-yl)-7-trifluoromethylimidazo1,2-α]pyrimidine

[0275] 2-Chloro-6-methoxypyridine (305 mg, 2.1 mmol) was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol)by the method of Example 1 to give3-(6-methoxypyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (43mg) as a white solid: δ_(H) (400 MHz, DMSO) 4.04 (3H, s), 6.84 (1H, d, J8.2), 7.73 (2H, t, J 6.7), 7.88 (1H, t, J 7.8), 8.81 (1H, s), 10.37 (1H,d, J 7.0); m/z (ES⁺) 295 (M⁺+H).

EXAMPLE 133-(6-Cyclopentylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0276] To 2,6-dibromopyridine (5.9 g, 25 mmol) andtetrakis(triphenylphosphine)palladium(0) (1.4 g, 1.2 mmol) was addedcyclopentylzinc bromide (50 ml, 0.5 M solution in tetrahydrofuran) andthe mixture heated at reflux for 18 h. The reaction was diluted withethyl acetate and washed with water. The organic phase was separated,dried over magnesium sulfate, filtered and evaporated in vacuo to givean oil. The crude product was chromatographed on silica, eluting on agradient from 1 to 5% methanol in dichloromethane, to give2-bromo-6-cyclopentylpyridine (3.25 g) as a white solid: δ_(H) (400 MHz,CDCl₃) 1.60-1.90 (6H, m), 2.09 (2H, m), 3.17 (1H, m), 7.12 (1H, d, J7.4), 7.28 (1H, d, J 7.4), 7.44 (1H, t, J 7.2); m/z (ES⁺) 226:228 (1:1)(M⁺+H).

[0277] 2-Bromo-6-cyclopentylpyridine (479 mg, 2.1 mmol) was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol)by the method of Example 1 to give3-(6-cyclopentylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine(49 mg) as a white solid: δ_(H) (400 MHz, DMSO) 1.70-1.87 (6H, m),2.10-2.16 (2H, m), 7.29 (1H, d, J 7.4), 7.80 (1H, d, J 7.0), 7.87 (1H,t, J 7.8), 7.95-7.97 (1H, m), 8.84 (1H, s), 10.50 (1H, d, J 6.7); m/z(ES⁺) 332 (M⁺+H).

EXAMPLE 143-(5-Methylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0278] 2-Bromo-5-methylpyridine (1.29 g, 7.5 mmol) was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (3.8 mmol)by the method of Example 1. Purification by chromatography on silica geleluting with dichloromethane containing 1% methanol, thencrystallisation from toluene/isohexane, gave3-(5-methylpyridin-2-yl)-7-trifluoromethyl-imidazo[1,2-α]pyrimidine as ayellow solid: δ_(H) (400 MHz, CDCl₃) 10.48 (1H, d, J 7), 8.50-8.52 (1H,m), 8.46 (1H, s), 7.72 (1H, d, J 8), 7.61-7.65 (1H, m), 7.31 (1H, d, J7); m/z (ES⁺) 279 (M⁺+H).

EXAMPLE 157-Trifluoromethyl-3-(5-trifluoromethylpyridin-2-yl)imidazo[1,2-α]pyrimidine

[0279] 2-Bromo-5-trifluoromethylpyridine (1.70 g, 7.5 mmol) was coupledto 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (3.8mmol) by the method of Example 1. Purification by chromatography onsilica gel eluting with dichloromethane containing 1% methanol, thencrystallisation from toluene, gave7-trifluoromethyl-3-(5-trifluoromethylpyridin-2-yl)imidazo[1,2-α]pyrimidineas a yellow solid: δ_(H) (400 MHz, CDCl₃) 10.52 (1H, d, J 7), 8.94-8.97(1H, m), 8.63 (1H, s), 8.03-8.07 (1H, m), 7.96 (1H, d, J 9), 7.41 (1H,d, J 7); m/z (ES⁺) 333 (M⁺+H).

EXAMPLE 162-[4-(7-Trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyrimidin-2-yl]-benzonitrile

[0280] To a degassed solution of the product of Example 5 (70 mg, 0.23mmol) in N,N-dimethylacetamide (2 ml) was added2-tributylstannylbenzonitrile (183 mg, 0.46 mmol), lithium chloride(27.5 mg, 0.58 mmol), copper(I) iodide (5 mg) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (9 mg) andthe mixture heated at 90° C. for 4 h. After cooling to ambienttemperature the reaction was poured onto a strong cation exchangecartridge and eluted with methanol. The product was then eluted with a2.0M solution of ammonia in methanol and evaporated in vacuo. Theresidue was dissolved in 5% methanol in dichloromethane and applied totwo preparative TLC plates (silica gel) and eluted with 1:1 ethylacetate in isohexane. The appropriate band was collected and processedto give a solid which was recrystallised from dichloromethane/ethylacetate/isohexane to give2-[4-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyrimidin-2-yl]benzonitrile(10 mg) as a white solid: δ_(H) (400 MHz, CDCl₃) 7.50 (1H, d, J 7.4),7.65-7.69 (1H, m), 7.78-7.82 (2H, m), 7.94 (1H, dd, J 7.8 and 1.2), 8.34(1H, dd, J 8.0 and 1.0), 8.74 (1H, s), 8.97 (1H, d, J 5.5), 10.74 (1H,d, J 7.4); m/z (ES⁺) 366 (M⁺+H).

EXAMPLE 173-[3-(Thien-2-yl)-[1,2,4]thiadiazol-5-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0281] A solution of ^(i)PrMgCl (2.0M in THF, 1.13 ml, 2.26 mmol) wasadded dropwise to a stirred suspension of3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine (547 mg, 2.06 mmol) inTHF (20 ml) at −78° C. under N₂. The resulting solution was stirred at−78° C. for 15 min and then tributyltin chloride (670 μl, 2.47 mmol) wasadded. The reaction was warmed to 0° C. and stirred for 1 h.5-Chloro-3-(thien-2-yl)-[1,2,4]thiadiazole (500 mg, 2.47 mmol) andtetrakis(triphenylphosphine)palladium(0) (237 mg, 0.21 mmol) were addedand the reaction heated at reflux for 1 h. Copper(I) iodide (50 mg, 0.26mmol) was added and heating continued for a further 1.5 h. The mixturewas concentrated under reduced pressure while dry loading onto silica.The resulting crude residue was purified by column chromatography onsilica, using 50% EtOAc in hexane as the eluent, and subsequentrecystallisation from dichloromethane/isohexanes gave3-[3-(thien-2-yl)-[1,2,4]thiadiazol-5-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine(188 mg, 26%): δ_(H) (400 MHz, d⁶-DMSO) 7.30 (1H, t, J 3.7), 7.83-7.90(2H, m), 8.11 (1H, dd, J 3.7 and 1.1), 9.14 (1H, s), 10.20 (1H, d, J7.1); m/z (ES⁺) 353 (M⁺).

EXAMPLE 183-[4-(Pyridin-3-yl)thien-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0282] 3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine (547 mg, 2.06mmol) was reacted with 2,4-dibromothiophene over 1 h as described inExample 17. The resulting crude residue was purified by columnchromatography on silica, using 40% EtOAc in isohexanes as the eluent,to yield 3-(4-bromothien-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine(104 mg, 15%) after recystallisation from dichloromethane/isohexanes:δ_(H) (400 MHz, d⁶-DMSO) 7.57 (1H, d, J 8.3), 7.72 (1H, d, J 1.6), 8.10(1H, d, J 1.6), 8.34 (1H, s), 9.34 (1H, d, J 7.0); m/z (ES⁺) 347, 349(1:1) (M⁺).

[0283] A mixture of3-(4-bromothien-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (104 mg,0.3 mmol), pyridine-3-boronic acid-1,3-propanediol cyclic ester (73 g,0.45 mmol), cesium carbonate (0.29 g, 0.9 mmol) andtetrakis(triphenylphosphine)palladium(0) (34 mg, 0.03 mmol) in1,4-dioxane (5 ml) and H₂O (0.5 ml) were degassed with a stream of N₂for 10 min. The reaction mixture was then heated at reflux for 1 h. Themixture was concentrated under reduced pressure to remove the organicsolvents and H₂O (20 ml) was added. The organics were extracted withdichloromethane (2×50 ml) and concentrated under reduced pressure whiledry loading onto silica. The resulting crude residue was purified bycolumn chromatography on silica using 70% EtOAc in hexanes containing 1%Et₃N and 1% MeOH as the eluent. The resulting material was taken up inMeOH and was poured onto a strong cation exchange cartridge and elutedwith methanol. The product was then eluted with 2.0M NH₃ in MeOH andevaporated to give3-[4-(pyridin-3-yl)thien-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine(83 mg, 80%): δ_(H) (400 MHz, d⁶-DMSO) 7.46-7.53 (1H, m), 7.60 (1H, d, J7.1), 8.18 (1H, d, J 1.5), 8.22-8.30 (1H, m), 8.26 (1H, d, J 1.5), 8.42(1H, s), 8.56-8.60 (1H, m), 9.10 (1H, s), 10.20 (1H, d, J 7.1); m/z(ES⁺) 346 (M⁺).

EXAMPLE 193-[5-(Pyridin-3-yl)thien-3-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0284] A mixture of 2,4-dibromothiophene (3 g, 12.4 mmol) andpyridine-3-boronic acid-1,3-propanediol cyclic ester (2.22 g, 13.6 mmol)in EtOH (30 ml) and toluene (30 ml) together with 2N Na₂CO₃ solution(12.4 ml) was degassed with a stream of N₂ for 10 min.Tetrakis-(triphenylphosphine)palladium(0) (0.25 g, 0.22 mmol) was addedand the reaction heated at reflux for 4 h. The mixture was concentratedunder reduced pressure to remove the organic solvents and H₂O (100 ml)was added. The organics were extracted with EtOAc (200 ml) and thenwashed with brine (75 ml), dried (MgSO₄), and concentrated under vacuum.The resulting crude residue was purified by column chromatography onsilica using 70% diethyl ether in hexane as the eluent to yield3-(4-bromothien-2-yl)pyridine (2.15 g, 75%): δ_(H) (360 MHz, CDCl₃) 7.26(1H, s), 7.32 (1H, dd, J 8.6 and 4.9), 7.81 (1H, dt, J 8.6 and 1.7),8.56 (1H, s), 8.86 (1H, s); m/z (ES⁺) 240, 242 (1:1) (M⁺+H).

[0285] A mixture of 3-(4-bromothien-2-yl)pyridine (948 mg, 4.0 mmol),bis-(neopentyl glycolato)diborane (985 g, 4.36 mmol), KOAc (1.16 g, 11.8mmol) and Pd(dppf)Cl₂ (161 mg, 5 mol %) in 1,4-dioxane (50 ml) wasdegassed with a stream of N₂ for 10 min and then heated at 110° C. for 3h. The reaction mixture was concentrated under reduced pressure and H₂O(100 ml) was added, and then was extracted with diethyl ether (2×75 ml).The combined ethereal extracts were washed with brine (50 ml) and dried(MgSO₄) to yield3-[4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)thien-2-yl]pyridine (927 mg,85%): δ_(H) (360 MHz, CDCl₃) 1.03 (6H, 8), 3.77 (4H, s), 7.30 (1H, dd, J7.6 and 4.4), 7.62 (1H, s), 7.83 (1H, s), 7.88 (1H, dt, J 7.6 and 1.8),8.51 (1H, s), 8.91 (1H, s); m/z (ES⁺) 273, 274 (1:4) (M⁺+H).

[0286] A mixture of 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine(250 mg, 0.94 mmol), the foregoing boronate ester (537 mg, 1.88 mmol)and K₃PO₄ (866 mg, 3.76 mmol) in N,N-dimethylacetamide (6 ml) wasdegassed with a stream of N₂ for 5 min and thentetrakis(triphenylphosphine)palladium(0) (109 mg, 10 mol %) was addedand the reaction was heated at 60° C. for 1 h. EtOAc (100 ml) was addedand the mixture washed with H₂O (3×100 ml) and brine (100 ml), dried(MgSO₄) and concentrated under reduced pressure while dry loading ontosilica. The residue was purified by column chromatography on silicausing 70% EtOAc in hexanes containing 1% Et₃N and 1% MeOH as the eluent.The resulting material was taken up in MeOH and was poured on to astrong cation exchange cartridge and eluted with methanol. The productwas then eluted with 2.0M NH₃ in MeOH and evaporated while dry loadingonto silica. Subsequent purification by column chromatography on silicausing 70% EtOAc in dichloromethane gave3-[5-(pyridin-3-yl)thien-3-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine(129 mg, 40%): δ_(H) (400 MHz, d₆-DMSO) 7.46-7.54 (1H, m), 7.58 (1H, d,J 7.1), 8.16-8.20 (1H, m), 8.20 (1H, s), 8.41 (1H, s), 8.56 (1H, dd, J4.7 and 1.4), 9.04 (1H, s), 9.45 (1H, d, J 7.1); m/z (ES⁺) 347 (M⁺+H).

EXAMPLE 203-[4-(Pyridin-3-yl)thiazol-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0287] A mixture of 2-amino-4-trifluoromethylpyrimidine (2.0 g, 12.2mmol) and N,N-dimethylformamide dimethyl acetal (1.79 ml, 13.5 mmol) intoluene (50 ml) was heated at reflux for 1 h and then concentrated underreduced pressure. The resulting formamide was treated with ethylbromoacetate (1.49 ml, 13.4 mmol) in toluene (60 ml) at reflux for 12 hand then concentrated under reduced pressure. The product was treatedwith saturated sodium hydrogencarbonate solution (50 ml) and extractedwith EtOAc (3×50 ml). The combined organic extracts were washed withbrine (50 ml), dried (MgSO₄) and then concentrated while dry loadingonto silica. Subsequent purification by column chromatography on silicausing diethyl ether gave ethyl7-trifluoromethylimidazo[1,2-α]pyrimidine-3-carboxylate (2.01 g, 64%):δ_(H) (360 Mz, CDCl₃) δ 1.45 (3H, t, J 7.1), 4.47 (2H, q, J 7.1), 7.44(1H, d, J 7.1), 8.60 (1H, s), 9.77 (1H, d, J 7.1); m/z (ES⁺) 347 (M⁺+H).

[0288] A mixture of the foregoing ethyl ester (1.58 g, 6.1 mmol) andammonia solution (25%, 50 ml) in EtOH (200 ml) was stirred at roomtemperature for 72 h. The organic solvent was removed under reducedpressure and the aqueous extracted with EtOAc (3×250 ml). The combinedorganic extracts were washed with brine (100 ml), dried (MgSO₄) and thenconcentrated while dry loading onto silica. Subsequent purification bycolumn chromatography on silica using EtOAc/ether gave7-trifluoromethylimidazo[1,2-α]pyrimidine-3-carboxamide (160 mg, 10%):δ_(H) (360 MHz, d₆-DMSO) 7.70 (1H, d, J 7.1), 7.72 (1H, s), 8.28 (1H,s), 8.69 (1H, s), 10.02 (1H, d, J 7.1).

[0289] Lawesson's reagent (281 mg, 0.7 mmol) was added to a stirredsuspension of the foregoing amide (160 mg, 0.7 mmol) in toluene (16 ml).The resulting mixture was heated at reflux for 2.5 h and thenconcentrated under reduced pressure while dry loading onto silica.Subsequent purification by column chromatography on silica using firstlydiethyl ether and then EtOAc/ether gave7-trifluoromethylimidazo[1,2-α]pyrimidine-3-carbothioamide (160 mg,93%): δ_(H) (360 MHz, d⁶-DMSO) δ 7.80 (1H, d, J 7.2), 8.70 (1H, s), 9.73(1H, s), 9.82 (1H, s), 10.87 (1H, d, J 7.2).

[0290] 3-(Bromoacetyl)pyridinium bromide (41 mg, 0.14 mmol) was added toa stirred solution of the foregoing thioamide (24 mg, 0.1 mmol) in DMF(1 ml) at room temperature under N₂. The reaction was warmed to 60° C.for 1 h and then concentrated under reduced pressure while azeotropingwith xylene (20 ml). The crude residue was taken up in EtOAc (50 ml),washed with saturated sodium hydrogencarbonate solution (20 ml) andconcentrated under reduced pressure while dry loading onto silica.Subsequent purification by column chromatography on silica using 70%EtOAc in hexanes containing 1% Et₃N and 1% MeOH as the eluent gave3-[4-(pyridin-3-yl)thiazol-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine(33 mg, 97%): δ_(H) (400 MHz, d⁶-DMSO) 7.52-7.60 (1H, m), 7.80 (1H, d, J7.1), 8.43 (1H, s), 8.50 (1H, dt, J 7.8 and 2.0), 8.62 (1H, m), 8.83(1H, s), 9.39 (1H, s), 10.33 (1H, d, J 7.1); m/z (ES⁺) 347 (M⁺).

EXAMPLE 212-{6-[7-(1-Hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile

[0291] A solution of 3-hydroxy-3-methyl-2-butanone (10.75 ml, 100 mmol)and triethylamine (21 ml, 150 mmol) in dichloromethane (125 ml) wastreated with acetic anhydride (11.8 ml, 125 mmol) then with4-dimethylaminopyridine (610 mg, 5 mmol) and the reaction was stirred atambient temperature for 14 h. Methanol (10 ml) was added and stirringcontinued for 30 min before concentrating the reaction in vacuo. Theresidue was dissolved in ether (300 ml) and washed with 0.5Nhydrochloric acid (2×300 ml), water, saturated aqueous sodiumhydrogencarbonate, dried over anhydrous magnesium sulfate, filtered andevaporated to dryness to afford acetic acid 1,1-dimethyl-2-oxopropylester as a yellow liquid (13.5 g, 94%): δ_(H) (400 MHz, CDCl₃) 1.46 (6H,s), 2.09 (3H, s), 2.12 (3H, s).

[0292] Boron trifluoride etherate (17.03 g, 120.0 mmol) was addeddrop-wise over 15 min to a cooled (−40° C.) solution of triethylorthoformate (14.82 g, 100.0 mmol) in dichloromethane (50 ml). Stirringwas continued for 10 min then the solution was transferred to anice-water bath and stirred at 0° C. for 20 min. The mixture was cooledto −78° C., and acetic acid 1,1-dimethyl-2-oxopropyl ester (7.21 g, 50.0mmol) added followed by drop-wise addition of N,N-diisopropylethylamine(19.39 g, 150.0 mmol) over 15 min. Stirring was continued for 1 h thenthe solution was poured onto a vigorously stirred mixture of saturatedsodium hydrogencarbonate solution (500 ml) and dichloromethane (200 ml).The organic phase was separated, washed with ice-cold 1N sulfuric acidsolution (2×500 ml) and ice-cold water (2×500 ml), dried over anhydroussodium sulfate solution and evaporated to give acetic acid4,4-diethoxy-1,1-dimethyl-2-oxobutyl ester (12.32 g, 100%) as a yellowoil.

[0293] Sodium methoxide (3.11 g, 57.5 mmol) was added to a stirredsolution of 2-aminoimidazole hemisulfate (6.61 g, 25.0 mmol) and aceticacid 4,4-diethoxy-1,1-dimethyl-2-oxobutyl ester (12.32 g, 50.0 mmol) inethanol (50 ml). The mixture was heated under reflux for 16 h, allowedto cool to ambient temperature then pre-adsorbed directly onto silica.Purification by silica gel chromatography eluting with dichloromethaneand 1% conc. ammonia on a gradient of methanol (1-3%) gave2-(imidazo[1,2-α]pyrimidin-7-yl)propan-2-ol as an orange solid: δ_(H)(400 MHz, CDCl₃) 1.60 (6H, s), 5.31 (1H, s), 7.10 (1H, d, J 7), 7.54(1H, d, J 1), 7.72 (1H, d, J 1), 8.49 (1H, d, J 7).

[0294] 2-(Imidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was brominated asdescribed in Example 1 to give2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)-propan-2-ol as an off-whitesolid: δ_(H) (400 MHz, CDCl₃) 1.62 (6H, s), 4.20 (1H, s), 7.17 (1H, d, J7), 7.76 (1H, s), 8.40 (1H, d, J 7).

[0295] Triethylsilyl trifluoromethanesulfonate (4.85 ml, 21.5 mmol) wasadded dropwise over 15 min to a cooled (−50° C.) solution of2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (5.0 g, 19.5 mmol)and diisopropylethylamine (4.76 ml, 27.5 mmol) in dichloromethane (150ml). The mixture was stirred for 20 min then allowed to warm to ambienttemperature overnight. The reaction mixture was diluted withdichloromethane (100 ml) and washed with 1N hydrochloric acid (100 ml)and water (100 ml), dried over anhydrous magnesium sulfate, filtered andevaporated. The red oil was purified by dry flash column chromatographyon silica eluting with dichloromethane on a gradient of methanol (0-3%).Collecting the appropriate fractions gave3-bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidineas a pale yellow oil which crystallised on standing (6.21 g, 86%): δ_(H)(400 MHz, CDCl₃) 0.64 (6H, q, J 8), 0.97 (9H, t, J 8), 7.50 (1H, d, J7), 7.72 (1H, s), 8.35 (1H, d, J 7).

[0296]7-(1-Methyl-1-triethylsilanyloxyethyl)-3-tributylstannyl-imidazo[1,2-α]pyrimidinewas prepared from3-bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidinein the same way as described in Example 1: m/z (ES⁺) 578, 580, 582(M⁺+H).

[0297] 2,6-Dibromopyridine was coupled with7-(1-methyl-1-triethylsilanyloxyethyl)-3-tributylstannylimidazo[1,2-α]pyrimidineby the method of Example 1 to afford3-(6-bromopyridin-2-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidineas an orange oil: δ_(H) (360 MHz, CDCl₃) 0.69 (6H, q, J 8), 0.99 (9H, q,J 8), 1.69 (6H, s), 7.34 (1H, d, J 7), 7.54-7.62 (2H, m), 7.69 (1H, d, J8), 8.29 (1H, s), 10.00 (1H, d, J 7).

[0298] A mixture of 2-bromobenzonitrile (18.2 g, 100 mmol), potassiumacetate (19.63 g, 200 mmol), bis(pinacolato)diboron (27.93 g, 110 mmol)and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (1.63 g, 2 mmol) in 1,4-dioxane (300 mlcontaining 6 ml dimethylsulfoxide) was degassed with nitrogen for 1 hthen heated at 90° C. for) 14 h. The reaction was cooled to ambienttemperature and then concentrated in vacuo. The residue was stirred with2N sodium hydroxide (1 l) for 10 min then filtered. The filtrate wasextracted with diethyl ether (2×300 ml) and the organics discarded. Theaqueous component was cooled to 0° C. then treated with 5N hydrochloricacid added dropwise over 15 min until pH 8. The aqueous phase wasextracted with ethyl acetate (2×200 ml), the combined organics weredried over anhydrous sodium sulfate, filtered and evaporated to afford2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (12.5 g,55%) as a pale brown solid: δ_(H) (400 MHz, CDCl₃) 1.38 (12H, s),7.47-7.58 (2H, m), 7.69 (1H, dd, J 9 and 2), 7.88 (1H, dd, J 9 and 2).

[0299]3-(6-Bromopyridin-2-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidinewas coupled to2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile followingthe procedure in Example 2 to give2-{6-[7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrileas an orange oil.

[0300] To a solution of crude2-{6-[7-(1-methyl-1-triethylsilanyloxy-ethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrilein ethanol (3 ml) was added 3 drops of concentrated hydrochloric acidand the mixture left to stir at ambient temperature for 18 h. Thesolvent was evaporated and the residue made basic by the addition ofsaturated aqueous sodium hydrogencarbonate. The aqueous phase wasdiluted with water (30 ml) and extracted with ethyl acetate (2×75 ml).The combined organic phase was washed with water (30 ml) and brine (30ml), dried over anhydrous sodium sulfate, filtered and evaporated togive an orange oil. This oil was purified on silica eluting withdichloromethane (+1% 0.880 ammonia) on a gradient of methanol (1-3%).Collecting the appropriate fractions followed by recrystallisation fromethyl acetate/isohexane gave2-{6-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrileas a white solid: δ_(H) (360 MHz, CDCl₃) 1.63 (6H, s), 4.52 (1H, s),7.16 (1H, d, J 7), 7.55-7.62 (2H, m), 7.74-7.96 (5H, m), 8.36 (1H, s),10.37 (1H, d, J 7); m/z (ES⁺) 356 (M⁺+H).

EXAMPLE 225-Fluoro-2-{6-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile

[0301]3-(6-Bromopyridin-2-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidine(336 mg, 0.75 mmol) was coupled to5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile(synthesised from 2-bromo-5-fluorobenzonitrile as in Example 21)following the procedure in Example 2 to give5-fluoro-2-{6-[7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrileas an orange oil.

[0302]5-Fluoro-2-{6-[7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrilewas deprotected using the procedure in Example 21 to give5-fluoro-2-{6-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile(80 mg, 29%) as a white solid: δ_(H) (400 MHz, CDCl₃) 1.63 (6H, s), 4.48(1H, s), 7.16 (1H, d, J 7), 7.46 (1H, ddd, J 8, 5 and 1), 7.54 (1H, d, J8), 7.59 (1H, dd, J 8 and 1), 7.80 (1H, dd, J 8 and 8), 7.86 (1H, dd, J8 and 1), 7.94 (1H, dd, J 8 and 8), 8.37 (1H, s), 10.30 (1H, d, J 7);m/z (ES⁺) 374 (M⁺+H). EXAMPLE 23

3-{6-[7-(1-Hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}thiophene-2-carbonitrile

[0303]3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)thiophene-2-carbonitrilewas synthesised following the procedure in Example 21 from3-bromo-2-cyanothiophene.3-(6-Bromopyridin-2-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidinewas coupled to3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)thiophene-2-carbonitrilefollowing the procedure in Example 2 to give3-{6-[7-(1-methyl-1-triethylsilanyl-oxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}thiophene-2-carbonitrileas an orange oil.

[0304]3-{6-[7-(1-Methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}thiophene-2-carbonitrilewas deprotected using the procedure in Example 21 to give3-{6-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}thiophene-2-carbonitrile(159 mg, 59%) as a pale brown solid: δ_(H) (360 MHz, CDCl₃) 1.64 (6H,s), 4.53 (1H, s), 7.20 (1H, d, J 7), 7.59 (1H, d, J 5), 7.67-7.71 (2H,m), 7.84 (1H, d, J 8), 7.92 (1H, dd, J 8 and 8), 8.35 (1H, s), 10.36(1H, d, J 7); m/z (ES⁺) 362 (M⁺+H).

EXAMPLE 244-Fluoro-2-{6-[7-(1-hydroxy-1-methylethyl)imidazo[1.2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile

[0305]4-Fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrilewas synthesised from 2-bromo-4-fluorobenzonitrile following theprocedure in Example 22.3-(6-Bromopyridin-2-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidinewas coupled to4-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrilefollowing the procedure in Example 2 to give4-fluoro-2-{6-[7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrileas an orange oil.

[0306]4-Fluoro-2-{6-[7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrilewas deprotected using the procedure in Example 21 to give4-fluoro-2-{6-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile(195 mg, 65%) as a white solid: δ_(H) (360 MHz, CDCl₃) 1.63 (6H, s),4.48 (1H, s), 7.18 (1H, d, J 7), 7.29 (1H, ddd, J 8, 2 and 1), 7.52 (1H,dd, J 9 and 2), 7.59 (1H, dd, J 8 and 1), 7.87-7.98 (3H, m), 8.37 (1H,s), 10.31 (1H, d, J 7); m/z (ES⁺) 374 (M⁺+H).

EXAMPLE 253-(6-Bromopyridin-2-yl)-7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine

[0307] 3-Fluoro-3-methylbutan-2-one was prepared from3-bromo-3-methylbutan-2-one as described by Fry and Migron (TetrahedronLett., 1979, 3357-3360) to give 3-fluoro-3-methylbutan-2-one as acolourless oil (contaminated with 6% 3-methyl-3-buten-2-one): bp 74-6°C.; δ_(H) (360 MHz, CDCl₃) 1.45 (6H, d, J 22), 2.28 (3H, d, J 5).

[0308] 3-Fluoro-3-methylbutan-2-one (5.75 g, 55.2 mmol) was converted to1,1-diethoxy-4-fluoro-4-methylpentan-3-one as described in Example 21and condensed with 2-aminoimidazole hemisulfate as in Example 21 to give7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine as an orange oilwhich crystallised on standing (7.41 g, 75%): δ_(H) (400 MHz, CDCl₃)1.77 (6H, d, J 22), 7.21 (1H, dd, J 7 and 2), 7.54 (1H, d, J 1), 7.79(1H, d, J 1), 8.45 (1H, d, J 7).

[0309] 7-(1-Fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine (2.0 g, 11.1mmol) was brominated as described in Example 1 to give3-bromo-7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine (1.65 g, 58%)as an off-white solid: δ_(H) (360 MHz, CDCl₃) 1.78 (6H, d, J 22), 7.35(1H, d, J 7 and 2), 7.77 (1H, s), 8.42 (1H, d, J 7).

[0310]7-(1-Fluoro-1-methylethyl)-3-tributylstannylimidazo[1,2-α]pyrimidine wasprepared from3-bromo-7-(1-fluoro-1-methyl-ethyl)imidazo[1,2-α]pyrimidine (1.13 g,4.38 mmol) in the same way as described in Example 1: m/z (ES⁺) 580,582, 584 (M⁺+H).

[0311] 2,6-Dibromopyridine was coupled with7-(1-fluoro-1-methylethyl)-3-tributylstannylimidazo[1,2-α]pyrimidine bythe method of Example 1 to afford3-(6-bromopyridin-2-yl)-7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine(1.0 g, 68%) as a pale yellow solid: δ_(H) (360 MHz, CDCl₃) 1.81 (6H, d,J 22), 7.37 (1H, d, J 8), 7.42 (1H, dd, J 7 and 2), 7.61 (1H, dd, J 8and 8), 7.71 (1H, dd, J 8 and 1), 8.33 (1H, s), 10.09 (1H, d, J 7).

EXAMPLE 262-{6-[7-(1-Fluoro-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile

[0312] The product of Example 25 (0.34 g, 1.0 mmol) was coupled to2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile followingthe procedure in Example 2 to give2-{6-[7-(1-fluoro-1-methyl-ethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl)benzonitrile(0.133 g, 37%) as a white solid: δ_(H) (360 MHz, CDCl₃) 1.80 (6H, d, J22), 7.38 (1H, dd, J 7 and 2), 7.59 (1H, ddd, J 8, 7 and 1), 7.75 (1H,ddd, J 8, 7 and 1), 7.80-7.96 (5H, m), 8.38 (1H, s), 10.36 (1H, d, J 7);m/z (ES⁺) 358 (M⁺+H).

EXAMPLE 272-{6-[7-(1-Cyano-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile

[0313] 2,6-Dibromopyridine (0.47 g, 2.0 mmol),2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (0.69 g,3.0 mmol) and potassium phosphate (0.85 g, 4.0 mmol) were dissolved inN,N-dimethylformamide (10 ml) and degassed with nitrogen for 15 min.

[0314] Tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol) wasadded then the mixture heated at 80° C. for 16 h. The mixture wasallowed to cool to ambient temperature, diluted with water (200 ml) andextracted into ethyl acetate (2×150 ml). The combined organics werewashed with brine (200 ml), dried over anhydrous sodium sulfate andevaporated to give a yellow oil. Purification by flash columnchromatography on silica eluting with isohexane on a gradient of ethylacetate (10-30%) gave 2-(6-bromopyridin-2-yl)benzonitrile (0.518 g,100%) as a waxy solid: δ_(H) (360 MHz, CDCl₃) 7.53-7.57 (2H, m),7.68-7.72 (2H, m), 7.80 (1H, d, J 8), 7.86-7.90 (1H, m).

[0315] 2,2-Dimethyl-3-oxobutyronitrile was prepared from3-methyl-2-butanone as described by Rasmussen (Synthesis, 1973, 682): bp74-6° C. (30 mmHg); δ_(H) (360 MHz, CDCl₃) 1.51 (6H, s), 2.43 (3H, s).

[0316] 2,2-Dimethyl-3-oxobutyronitrile was converted to5,5-diethoxy-2,2-dimethyl-3-oxopentanenitrile then condensed with2-aminoimidazole hemisulfate following the procedure in Example 21 togive 2-(imidazo[1,2-α]pyrimidin-7-yl)-2-methylpropionitrile (5.15 g,69%) as a white solid: δ_(H) (400 MHz, CDCl₃) 1.84 (6H, s), 7.27 (1H, d,J 7), 7.58 (1H, d, J 1), 7.84 (1H, d, J 1), 8.49 (1H, d, J 7).

[0317] 2-(Imidazo[1,2-α]pyrimidin-7-yl)-2-methylpropionitrile (100 mg,0.51 mmol), 2-(6-bromopyridin-2-yl)benzonitrile (159 mg, 0.61 mmol) andcesium carbonate (332 mg, 1.02 mmol) were suspended in 1,4-dioxane anddegassed with nitrogen for 20 min.Tetrakis(triphenylphosphine)-palladium(0) (29 mg, 0.025 mmol) was addedand the mixture was heated at 80° C. for 3 h. The reaction was cooled toambient temperature then diluted with water (60 ml) and extracted withethyl acetate (2×100 ml). The combined organic extracts were washed withbrine (70 ml), dried over anhydrous sodium sulfate, filtered andevaporated to give a pale yellow oil. The oil was purified bychromatography on silica gel eluting with dichloromethane on a gradientof methanol (0-1%). Collecting appropriate fractions followed byrecrystallisation from ethyl acetate/isohexane gave2-{6-[7-(1-cyano-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile(70 mg, 38%) as a white solid: δ_(H) (360 MHz, CDCl₃) 1.86 (6H, s), 7.43(1H, d, J 7), 7.59-7.63 (2H, m), 7.80 (2H, m), 7.86-7.97 (3H, m), 8.42(1H, s), 10.44 (1H, d, J 7); m/z (ES⁺) 365 (M⁺+H).

EXAMPLE 282-[6-(7-tert-Butylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]-5-fluorobenzonitrile

[0318] 2,6-Dibromopyridine (1.17 g, 5.0 mmol) was coupled to5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile(synthesised as in Example 22) (1.48 g, 6.0 mmol) as described inExample 27 to afford 2-(6-bromopyridin-2-yl)-5-fluorobenzonitrile (0.69g, 50%) as a white solid: δ_(H) (400 MHz, CDCl₃) 1.42 (9H, s), 6.96 (1H,d, J 7), 7.45 (1H, d, J 1), 7.72 (1H, d, J 1), 8.33 (1H, d, J 7).

[0319] 3,3-Dimethylbutan-2-one was converted to1,1-diethoxy-4,4-dimethylpentan-3-one as described in Example 21 andcondensed with 2-aminoimidazole hemisulfate as described in Example 21to give 7-tert-butylimidazo[1,2-α]pyrimidine as a pale-orange solid:δ_(H) (400 MHz, CDCl₃) 1.42 (9H, s), 6.96 (1H, d, J 7), 7.45 (1H, d, J1), 7.72 (1H, d, J 1), 8.33 (1H, d, J 7).

[0320] 7-tert-Butylimidazo[1,2-α]pyrimidine was coupled with2-(6-bromopyridin-2-yl)-5-fluorobenzonitrile as described in Example 27to give2-[6-(7-tert-butylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]-5-fluorobenzonitrile(0.235 g, 63%) as a white powder: δ_(H) (360 MHz, CDCl₃) 1.43 (9H, s),7.05 (1H, d, J 7), 7.37-7.73 (6H, m), 7.81 (1H, s), 7.85 (1H, dd, J 8and 1), 8.75 (1H, d, J 7); m/z (ES⁺) 371 (M⁺+H).

EXAMPLE 294-Fluoro-2-[6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]benzonitrile

[0321]4-Fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile(synthesised as in Example 24) was coupled with 2,6-dibromopyridine asdescribed in Example 27 to give2-(6-bromopyridin-2-yl)-4-fluorobenzonitrile as a white solid: δ_(H)(360 MHz, d₆-DMSO) 7.55-7.60 (1H, m), 7.67-7.84 (2H, m), 7.89-8.02 (2H,m), 8.12 (1H, dd, J 9 and 6).

[0322] 3-Tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine wascoupled with 2-(6-bromopyridin-2-yl)-4-fluorobenzonitrile as in Example1 to give4-fluoro-2-[6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]benzonitrileas a pale pink solid (16 mg, 14%): δ_(H) (400 MHz, CDCl₃) 7.29-7.32 (1H,m), 7.40 (1H, d, J 7), 7.53 (1H, dd, J 9 and 2), 7.66 (1H, dd, J 8 and1), 7.88-8.03 (3H, m), 8.59 (1H, s), 10.56 (1H, d, J 7).

EXAMPLE 303-(2-Fluoropyridin-5-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0323] To a degassed solution of3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine was added5-bromo-2-fluoropyridine (0.128 ml, 1.3 mmol) andtetrakis(triphenylphosphine)palladium(0) (173 mg, 0.15 mmol) and themixture heated at reflux for 5 h. The crude reaction was washed withwater and extracted with ethyl acetate. After adding isohexane a darksolid was collected by suction filtration. The solid was adsorbed ontosilica and purified by chromatography on silica gel, eluting withisohexane on a gradient of ethyl acetate (20-60%), to give3-(2-fluoropyridin-5-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (150mg) as a dark solid: δ_(H) (500 MHz, CDCl₃) 7.12 (1H, m), 7.30 (1H, d, J7), 7.99-8.02 (1H, m), 8.10 (1H, s), 8.46 (1H, s), 8.72 (1H, d, J 7);m/z (ES⁺) 282, 283 (M⁺+H).

EXAMPLE 313-(2-Phenylpyridin-5-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0324] 3-Tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine wasreacted with 5-bromo-2-phenylpyridine (prepared according to theprocedure of Tilley and Zawoiski, J. Org. Chem., 1988, 53(2), 386-90) bythe method of Example 1 to afford3-(2-phenylpyridin-5-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine as ayellow solid: δ_(H) (400 MHz, CDCl₃) 7.30 (1H, d, J 7), 7.47-7.56 (3H,m), 7.96 (2H, m), 8.09 (2H, dd, J 8 and 1), 8.19 (1H, s), 8.83 (1H, d, J7), 8.93 (1H, d, J 2); m/z (ES⁺) 340 (M⁺+H).

EXAMPLE 323-[2-(4-Fluorophenyl)pyridin-5-yl)]-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0325] To a degassed mixture of 2,5-dibromopyridine (500 mg, 2.11 mmol)and 4-fluorobenzeneboronic acid (444 mg, 3.17 mmol) in ethylene glycoldimethyl ether (4.2 ml) and 2M aqueous sodium carbonate (2.1 ml) wasadded tetrakis(triphenylphosphine)palladium(0) (98 mg, 0.08 mmol). Thismixture was heated at reflux for 14 h. After cooling the crude reactionwas partitioned between water and dichloromethane. The organics weredried over anhydrous magnesium sulfate, filtered and adsorbed ontosilica. Purification by chromatography on silica gel, eluting with amixture of 4% diethyl ether in isohexane, gave5-bromo-2-(4-fluorophenyl)pyridine (470 mg) as a white solid: δ_(H) (360MHz, CDCl₃) 7.30 (1H, d, J 7), 7.12-7.19 (2H, m), 7.57 (1H, d, J 8),7.86 (1H, dd, J 2 and 8), 7.92-7.98 (2H, m), 8.72 (1H, d, J 2), m/z(ES⁺) 251, 252, 253, 254 (M⁺+H).

[0326] 3-Tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine wasreacted with 5-bromo-2-(4-fluorophenyl)pyridine by the method of Example1 to furnish3-[2-(4-fluorophenyl)pyridin-5-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine(47mg) as a yellow solid: δ_(H) (400 MHz, CDCl₃) 7.19-7.25 (2H, m), 7.31(1H, d, J 7), 7.90-7.97 (2H, m), 8.06-8.11 (2H, m), 8.19 (1H, s), 8.82(1H, d, J 7), 8.91 (1H, dd, J 2 and 1); m/z (ES⁺) 358, 359 (M⁺+H).

EXAMPLE 333-[2-(1H-Pyrrol-1-yl)pyridin-5-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0327] 3-Tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine wasreacted with 5-bromo-2-(pyrrol-1-yl)pyridine by the method of Example 1to afford3-[2-(1H-pyrrol-1-yl)pyridin-5-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidineas a yellow solid: δ_(H) (400 MHz, CDCl₃) 6.42 (2H, m), 7.28 (1H, d, J8), 7.52 (1H, dd, J 8 and 1), 7.58 (2H, m), 7.92 (1H, dd, J 8 and 2),8.14 (1H, s), 8.64 (1H, dd, J 2 and 1), 8.74 (1H, d, J 8), m/z (ES⁺)329, 330 (M⁺+H).

EXAMPLE 343-(2-Chloropyrimidin-4-yl)-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidine

[0328]7-(1-Methyl-1-triethylsilanyloxyethyl)-3-tributylstannyl-imidazo[1,2-α]pyrimidinewas reacted with 2,4-dichloropyrimidine by the method of Example 5 toafford3-(2-chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidineas a white solid: δ_(H) (400 MHz, CDCl₃) 0.70 (6H, q, J 8.0), 1.00 (9H,t, J 8.0), 1.69 (6H, s), 7.57 (1H, d, J 5.5), 7.67 (1H, d, J 7.0), 8.53(2H, m), 10.07 (1H, d, J 7.0); m/z (ES⁺) 403 (M⁺+H).

[0329] The foregoing compound was deprotected using the procedure ofExample 21 to afford3-(2-chloropyrimidin-4-yl)-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidineas a white solid: δ_(H) (400 MHz, CDCl₃) 1.65 (6H, s), 4.12 (1H, s),7.36 (1H, d, J 7.4), 7.61 (1H, d, J 5.1), 8.58 (2H, dd, J 6.7, 5.5),10.15 (1H, d, J 7.4), m/z (ES⁺) 290 (M⁺+H).

EXAMPLE 355-Fluoro-2-{4-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]-pyrimidin-2-yl}benzonitrile

[0330] To a degassed solution of3-(2-chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine(300 mg, 1.0 mmol) and5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile(371 mg, 1.5 mmol) (synthesised as in Example 22) in THF was addeddegassed sodium carbonate solution (2 ml) followed bytetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) and themixture heated at reflux for 2.5 hours. The reaction was diluted withdichloromethane (DCM) (20 ml) and washed with water (10 ml) and brine(10 ml). The organic phase was dried (Mg₂SO₄), filtered and evaporatedto give an orange oil. The crude product was chromatographed on silicaeluting on a gradient of 1-5% MeOH in DCM. Appropriate fractions werepooled and evaporated to give an off-white solid (163 mg). The solid wasrecrystallised from DCM/EtOAc to give5-fluoro-2-{4-[7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidin-3-yl]-pyrimidin-2-yl}benzonitrileas a cream-coloured solid (148 mg): δ_(H) (400 MHz, CDCl₃) 0.69 (6H, q,J 7.8), 0.99 (9H, t, J 7.8), 1.70 (6H, s), 7.49-7.52 (1H, m), 7.61 (1H,d, J 8.2), 7.62 (1H, d, J 7.0), 7.68 (1H, d, J 5.5), 8.34 (1H, dd, J5.5, 8.6), 8.53 (1H, s), 8.84 (1H, d, J 5.5), 10.28 (1H, d, J 7.4); m/z(ES⁺) 489 (M⁺+H).

[0331] The foregoing compound was deprotected using the procedure ofExample 21 to afford5-fluoro-2-{4-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl]benzonitrileas a white solid: δ_(H) (400 MHz, CDCl₃) 1.65 (6H, s), 4.27 (1H, s),7.32 (1H, d, J 7.4), 7.40-7.61 (2H, m), 7.71 (1H, d, J 5.5), 8.35 (1H,dd, J 5.5, 9.0), 8.55 (1H, s), 8.87 (1H, d, J 5.5), 10.40 (1H, d, J7.4); m/z (ES⁺) 375 (M⁺+H).

EXAMPLE 362-[3-(2-(Pyridin-3-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol

[0332]3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidinewas reacted with diethyl(3-pyridyl)borane by the method of Example 35 toafford7-(1-methyl-1-triethylsilanyloxyethyl)-3-[2-(pyridin-3-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidineas a white solid: δ_(H) (400 MHz, CDCl₃) 0.73 (6H, q, J 8.1), 1.01 (9H,t, J 8.0), 1.72 (6H, s), 7.46-7.53 (2H, m), 7.6 (1H, d, J 5.5), 7.67(1H, d, J 7.0), 8.52 (1H, s), 8.72-8.79 (2H, m), 9.71 (1H, m), 10.24(1H, d, J 7.0); m/z (ES⁺) 447 (M⁺+H).

[0333] The foregoing compound was deprotected using the procedure ofExample 21 to afford2-[3-(2-(pyridin-3-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-olas a white solid: δ_(H) (400 MHz, d⁶-DMSO) 1.55 (6H, s), 5.61 (1H, s),7.60-7.64 (1H, m), 7.76 (1H, d, J 7.4), 8.06 (1H, d, J 5.5), 8.75-8.78(1H, m), 8.78 (1H, s), 8.86 (1H, s), 8.92 (1H, d, J 5.5), 9.60 (1H, m),10.21 (1H, d, J 7.4); m/z (ES⁺) 333 (M⁺+H).

EXAMPLE 372-{4-[7-(1-Hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}thiophene-3-carbonitrile

[0334]3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidinewas reacted with2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)thiophene-3-carbonitrile(synthesised from 2-bromothiophene-3-carbonitrile following theprocedure in Example 21) by the method of Example 35 to afford2-{4-[7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}thiophene-3-carbonitrileas a white solid: δ_(H) (400 MHz, CDCl₃) 0.67 (6H, q, J 8.1), 0.99 (9H,t, J 8.0), 1.71 (6H, s), 7.66 (2H, m), 7.97 (1H, d, J 5.5), 8.51 (1H,s), 8.79 (1H, d, J 5.5), 9.71 (1H, m), 10.34 (1H, d, J 7.0); m/z (ES⁺)477 (M⁺+H).

[0335] The foregoing compound was deprotected using the procedure ofExample 21 to afford2-{4-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}thiophene-3-carbonitrileas a white solid: δ_(H) (400 MHz, d⁶-DMSO) 1.56 (6H, s), 7.85 (1H, d, J7.4), 8.09 (1H, d, J 5.5), 8.17 (1H, d, J 5.5), 8.21 (1H, d, J 5.5),9.04 (1H, d, J 5.5), 9.15 (1H, s), 10.35 (1H, d, J 7.0); m/z (ES⁺) 363(M⁺+H).

EXAMPLE 385-Fluoro-2-{4-[7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}benzonitrile

[0336]3-(2-Chloropyrimidin-4-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine wascoupled to5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile(synthesised as in Example 22) by the method of Example 1 to afford5-fluoro-2-{4-[7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}benzonitrileas a white solid: δ_(H) (400 MHz, CDCl₃) 7.48-7.53 (2H, m), 7.63 (1H,dd, J 2.5, 8.0), 7.78 (1H, d, J 5.5), 8.39 (1H, dd, J 5.5, 9.0), 8.74(1H, s), 8.95 (1H, d, J 5.5), 10.67 (1H, d, J 6.7); m/z (ES⁺) 385(M⁺+H).

EXAMPLE 392-[3-(2-Trifluoromethylpyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol

[0337] A solution of isopropylmagnesium chloride (2.0M in THF, 525 μl,1.05 mmol) was added dropwise to a stirred suspension of3-bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine(370 mg, 1.0 mmol) in THF (5 ml) at −78° C. under N₂. The resultingsolution was stirred at −78° C. for 15 min and then tributyltin chloride(298 μl, 1.1 mmol) was added. The reaction was warmed to 0° C. andstirred for 1 h. 4-Chloro-2-trifluoromethylpyrimidine (200 mg, 1.1 mmol)and tetrakis(triphenylphosphine)palladium(0) (110 mg, 10 mol %) wereadded and the reaction heated at reflux for 18 h. The mixture wasconcentrated under reduced pressure while dry loading onto silica andthen purified by column chromatography on silica using 50-80%EtOAc/isohexanes as the eluent to afford7-(1-methyl-1-triethylsilanyloxyethyl)-3-(2-trifluoromethylpyrimidin-4-yl)imidazo[1,2-α]pyrimidine(136 mg): ¹H NMR (400 MHz, CDCl₃) δ 10.10 (1H, d, J 7.4), 8.82 (1H, d, J5.5), 8.57 (1H, s), 7.78 (1H, d, J 5.5), 7.67 (1H, d, J 7.4), 1.70 (6H,s), 1.00 (9H, t, J 8.0), 0.68 (6H, q, J 8.0); m/z (ES⁺) 438 (M+H⁺).

[0338]7-(1-Methyl-1-triethylsilanyloxyethyl)-3-(2-trifluoromethylpyrimidin-4-yl)imidazo[1,2-α]pyrimidine(136 mg, 0.31 mmol) in EtOH (5 ml) was treated with conc. HCl (5 drops)and the mixture stirred at room temperature for 16 h. The resultingmixture was concentrated under reduced pressure and then NaHCO₃ solution(20 ml) added. The organics were extracted with CH₂Cl₂ (3×20 ml) andconcentrated under reduced pressure while dry loading onto MgSO₄. Theresidue was purified by column chromatography on silica using 5%MeOH/CH₂Cl₂ as the eluent to afford2-[3-(2-trifluoromethylpyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol(60 mg, 60%): ¹H NMR (400 MHz, d⁶-DMSO) δ 9.97 (1H, d, J 7.4), 9.00 (1H,d, J 5.6), 8.97 (1H, s), 8.35 (1H, d, J 5.6), 7.73 (1H, d, J 7.4), 1.53(6H, s); m/z (ES⁺) 324 (M+H⁺).

EXAMPLE 402-[3-(2-(Thiazol-2-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol

[0339] A solution of3-(2-chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine(prepared as in Example 34) (200 mg, 0.50 mmol) and2-tributylstannylthiazole (370 mg, 1.0 mmol) in THF (10 ml) was degassedwith a stream of N₂ for 10 min, thentetrakis(triphenylphosphine)palladium(0) (29 mg, 5 mol %) was added andthe reaction heated at reflux for 5 h. The mixture was concentratedunder reduced pressure while dry loading onto silica and then purifiedby column chromatography on silica using 100% EtOAc as the eluent toafford7-(1-methyl-1-triethylsilanyloxyethyl)-3-[2-(thiazol-2-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine(128 mg, 57%); m/z (ES⁺) 453 (M+H⁺).

[0340] The foregoing compound (128 mg, 0.28 mmol) was deprotected asdescribed in Example 39 to yield, after column chromatography on silicausing 5% MeOH(CH₂Cl₂,2-[3-(2-(thiazol-2-yl)pyrimidin-4yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol(54 mg, 56%): ¹H NMR (400 MHz, d⁶-DMSO) δ 10.37 (1H, d, J 7.2),8.90-8.83 (2H, m), 8.17 (1H, d, J 3.1), 8.11 (1H, d, J 5.6), 8.05 (1H,d, J 3.1), 7.71 (1H, d, J 7.2), 5.61 (1H, s), 1.55 (6H, s); m/z (ES⁺)339 (M+H⁺).

EXAMPLE 412-[3-(2-(Imidazol-1-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol

[0341] A solution of LiHMDS (370 μl) in hexanes (1.0M, 370 μmol) wasadded to a stirred solution of imidazole (25 mg, 0.37 mmol) and3-(2-chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine(from Example 34) (150 mg, 0.37 mmol) in THF (5 ml) at −78° C. under N₂.The reaction was allowed to warm slowly to room temperature overnightand was then quenched with NH₄Cl solution (10 ml). The organics wereextracted with EtOAc (2×25 ml), washed with brine (10 ml) andconcentrated under reduced pressure while dry loading onto silica. Theresidue was purified by column chromatography on silica using 100% EtOAcas the eluent to afford3-[2-(imidazol-1-yl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine(73 mg, 45%): ¹H NMR (400 MHz, d⁶-DMSO) δ 10.08 (1H, d, J 7.2), 8.93(1H, s), 8.85-8.78 (2H, m), 8.13 (1H, d, J 1.1), 8.03 (1H, d, J 5.5),7.72 (1H, d, J 7.2), 7.21 (1H, s), 1.64 (6H, s), 0.96 (9H, t, J 8.0),0.65 (6H, q, J 8.0); m/z (ES⁺) 453 (M+H⁺).

[0342] The foregoing compound (73 mg, 0.17 mmol) in EtOH (4 ml) wastreated with conc. HCl (4 drops) and the mixture stirred at roomtemperature for 7 h. The resulting mixture was concentrated underreduced pressure and then triturated with CH₂Cl₂ (15 ml) and filtered.NaHCO₃ solution (20 ml) was added to the solid and the organics wereextracted with CH₂Cl₂ (30 ml) and EtOAc (2×30 ml), then dried (MgSO₄)and concentrated under reduced pressure to afford2-[3-(2-(imidazol-1-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol(25 mg, 46%): ¹H NMR (400 MHz, d⁶-DMSO) δ 10.06 (1H, d, J 7.2), 8.92(1H, s), 8.83-8.78 (2H, m), 8.12 (1H, s), 8.03 (1H, d, J 5.0), 7.77 (1H,d, J 7.2), 7.21 (1H, s), 5.63 (1H, s), 1.54 (6H, s); m/z (ES⁺) 322(M+H⁺).

EXAMPLE 422-[3-(2-(Pyridin-4-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol

[0343]3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidine(from Example 34) (403 mg, 1.0 mmol), 4-tributylstannylpyridine (736 mg,2.0 mmol), tetrakis(triphenylphosphine)palladium(0) (115 mg, 10 mol %)and copper(I) iodide (115 mg) in 1,4-dioxane (20 ml) were heated atreflux overnight. Purification by column chromatography on silica using3-6% MeOH/CH₂Cl₂ as the eluent afforded7-(1-methyl-1-triethylsilanyloxyethyl)-3-[2-(pyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine:¹H NMR (400 MHz, d⁶-DMSO) δ 10.23 (1H, d, J 7.3), 8.98 (1H, d, J 5.4),8.89 (1H, s), 8.85-8.80 (2H, m), 8.36 (2H, d, J 5.9), 8.14 (1H, d, J5.5), 7.70 (1H, d, J 7.3), 1.65 (6H, s), 0.95 (9H, t, J 7.8), 0.66 (6H,q, J 7.8).

[0344]7-(1-Methyl-1-triethylsilanyloxyethyl)-3-[2-(pyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidinefrom above was treated with conc. HCl (10 drops) as described in Example39 to yield after purification by column chromatography on silica, using6% MeOH/CH₂Cl₂ as the eluent,2-[3-(2-(pyridin-4-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol(51 mg, 15%): ¹H NMR (360 MHz, d⁶-DMSO) δ 10.23 (1H, d, J 7.2), 8.98(1H, d, J 5.5), 8.88 (1H, s), 8.85-8.80 (2H, m), 8.36 (2H, dd, J 4.5,1.6), 8.14 (1H, d, J 5.5), 7.77 (1H, d, J 7.2), 5.62 (1H, s), 1.55 (6H,s); m/z (ES⁺) 333 (M+H⁺).

EXAMPLE 432-[3-(2-(Furan-2-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol

[0345]3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidine(from Example 34) (58 mg, 0.14 mmol) and 2-tributylstannylfuran (102 mg,0.29 mmol) were heated at reflux overnight as described in Example 40.Purification by column chromatography on silica using 70%EtOAc/isohexanes as the eluent gave3-[2-(furan-2-yl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine(36 mg, 57%): m/z (ES⁺) 435 (M+H⁺).

[0346] The foregoing compound (36 mg, 0.08 mmol) was deprotected asdescribed in Example 39 to yield, after column chromatography on silicausing 5% MeOH/CH₂Cl₂,2-[3-(2-(furan-2-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol(12 mg, 45%): ¹H NMR (360 MHz, d⁶-DMSO) δ 10.29 (1H, d, J 7.2),8.85-8.75 (2H, m), 7.99 (1H, broad s), 7.91 (1H, d, J 5.5), 7.72 (1H, d,J 7.2), 7.53 (1H, dd, J 3.5, 0.6), 6.77 (1H, dd, J 3.5, 1.7), 5.60 (1H,s), 1.54 (6H, s); m/z (ES⁺) 322 (M+H⁺).

EXAMPLE 442-[3-(2-(Furan-3-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol

[0347] A mixture of3-(2-chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine(from Example 34) (200 mg, 0.49 mmol), 3-furanboronic acid (111 mg, 0.98mmol), K₃PO₄ (457 mg, 1.96 mmol) andtetrakis(triphenylphosphine)palladium(0) (50 mg, 9 mol %) in DMA (6 ml)was heated at 90° C. for 45 min under N₂. The reaction was concentratedunder reduced pressure while azeotroping with xylene (3×30 ml). EtOAc(50 ml) and H₂O (50 ml) were added and the organics separated andconcentrated under reduced pressure while loading onto MgSO₄.Purification by column chromatography on silica using 3% MeOH/CH₂Cl₂ asthe eluent gave3-[2-(furan-3-yl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine(203 mg, 94%): m/z (ES⁺) 435 (M+H⁺).

[0348]3-[2-(Furan-3-yl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine(203 mg, 0.47 mmol) in EtOH (10 ml) was treated with conc. HCl (15drops) and the resulting solution was stirred at room temperature for 12h during which time a precipitate formed. The solid was filtered off andwas then partitioned between CH₂Cl₂ (20 ml) and NaHCO₃ solution (20 ml).The organic layer was separated and the aqueous extracted with CH₂Cl₂(3×20 ml). The combined organic extracts were dried (MgSO₄) andconcentrated under reduced pressure to afford2-[3-(2-(furan-3-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol(64 mg, 42%): ¹H NMR (400 MHz, d⁶-DMSO) δ 10.29 (1H, d, J 7.3), 8.81(1H, s), 8.77 (1H, d, J 5.4), 8.68 (1H, s), 7.89 (1H, d, J 5.4), 7.87(1H, s), 7.74 (1H, d, J 7.3), 7.20 (1H, s), 5.61 (1H, s), 1.54 (6H, s);m/z (ES⁺) 322 (M+H⁺).

EXAMPLE 452-{3-[2-(1-Oxypyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol

[0349] m-CPBA (50%, 154 mg, 0.45 mmol) was added to a stirred solutionof7-(1-methyl-1-triethylsilanyloxyethyl)-3-[2-(pyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine(200 mg, 0.45 mol) in CH₂Cl₂ (8 ml) and MeOH (2 ml). The reaction wasstirred at room temperature for 12 h, then was diluted with CH₂Cl₂ (200ml), washed with 1N NaOH (150 ml) and concentrated under reducedpressure while dry loading onto MgSO₄. Purification by columnchromatography on silica using first 5% EtOH/EtOAc to remove unreactedstarting material and then 5% MeOH/CH₂Cl₂ gave7-(1-methyl-1-triethylsilanyloxyethyl)-3-[2-(1-oxypyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine(111 mg, 54%): ¹H NMR (400 MHz, CDCl₃) δ 10.06 (1H, d, J 7.2), 8.78 (1H,d, J 5.5), 8.52 (1H, s), 8.39-8.31 (4H, m), 7.68 (2H, d, J 7.3), 7.60(1H, d, J 5.5), 1.72 (6H, s), 1.01 (9H, t, J 7.9), 0.69 (6H, q, J 7.9);m/z (ES⁺) 463 (M+H⁺).

[0350]7-(1-Methyl-1-triethylsilanyloxyethyl)-3-[2-(1-oxypyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine(140 mg, 0.30 mmol) was treated with conc. HCl (15 drops) as describedin Example 39 to yield, after purification by column-chromatography onsilica, using 10% MeOH/CH₂Cl₂ as the eluent,2-{3-[2-(1-oxypyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol(45 mg, 43%): ¹H NMR (360 MHz, d⁶-DMSO) δ 10.18 (1H, d, J 7.2), 8.93(1H, d, J 5.5), 8.88 (1H, s), 8.45-8.33 (2H, m), 8.06 (1H, d, J 5.5),7.73 (1H, d, J 7.2), 5.63 (1H, s), 1.55 (6H, s); m/z (ES⁺) 349 (M+H⁺).

EXAMPLE 463-[6-(1H-Imidazol-1-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0351] A stirred solution of 2,6-dibromopyridine (2.0 g, 8.3 mmol) andimidazole sodium salt (1.0 g, 10.5 mmol) in dimethylsulfoxide (10 ml)was heated at 100° C. for 36 h. After cooling to ambient temperature thereaction was diluted with water and extracted into dichloromethane.Combined organic extracts were washed with water and saturated brinethen dried over magnesium sulfate, filtered and evaporated in vacuo togive a solid. Purification by chromatography on silica gel eluting withdichloromethane, then dichloromethane containing 5% methanol, gave2-bromo-6-(1H-imidazol-1-yl)pyridine (0.18 g) as an off-white solid:δ_(H) (400 MHz, CDCl₃) 7.20 (1H, m), 7.32 (1H, d, J 8), 7.47 (1H, d, J8), 7.62 (1H, m), 7.68 (1H, dd, J 8 and 8), 8.35 (1H, s); m/z (ES⁺)224/226 (M⁺+H).

[0352] 2-Bromo-6-(1H-imidazol-1-yl)pyridine (0.18 g, 0.8 mmol) wascoupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine(0.9 mmol) by the method of Example 1. Purification by chromatography onsilica gel eluting with dichloromethane on a gradient of methanol(0-10%) and trituration with ethyl acetate gave3-[6-(1H-imidazol-1-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine(42 mg) as an off-white solid: δ_(H) (400 MHz, CDCl₃) 7.30 (1H, s), 7.35(1H, d, J 8), 7.43 (1H, d, J 7), 7.65 (1H, s), 7.79 (1H, d, J 8), 8.00(1H, dd, J 8 and 8), 8.38 (1H, s), 8.59 (1H, s), 10.24 (1H, d, J 7); m/z(ES⁺) 331 (M⁺+H).

EXAMPLE 473-[6-(Morpholin-4-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0353] A stirred solution of 2,6-dibromopyridine (5.0 g, 20.7 mmol),triethylamine (3.0 ml, 21.7 mmol) and morpholine (1.8 g, 20.7 mmol) indimethylsulfoxide (25 ml) was heated at 85° C. for 4 h. After cooling toambient temperature the reaction was poured into water. After decantingoff the aqueous, the gum was dissolved in dichloromethane, washed withwater and saturated brine, then dried over magnesium sulfate, filteredand evaporated in vacuo to give a solid. Purification by chromatographyon silica gel eluting with dichloromethane gave4-(6-bromopyridin-2-yl)morpholine (3.0 g) as a white solid: δ_(H) (400MHz, CDCl₃) 3.50 (4H, t, J 5), 3.80 (4H, t, J 5), 6.50 (1H, d, J 8),6.79 (1H, d, J 8), 7.31 (1H, dd, J 8 and 8); m/z (ES⁺) 242/244 (M⁺+H).

[0354] 4-(6-Bromopyridin-2-yl)morpholine (0.46 g, 1.9 mmol) was coupledto 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.8mmol) by the method of Example 1. Purification by chromatography onsilica gel eluting with dichloromethane on a gradient of methanol(0-10%) and crystallisation from ethyl acetate-isohexane gave3-[6-(morpholin-4-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine(220 mg) as a yellow solid: δ_(H) (400 MHz, CDCl₃) 3.57 (4H, t, J 5),3.90 (4H, t, J 5), 6.65 (1H, d, J 8), 7.20 (1H, d, J 8), 7.33 (1H, d, J7), 7.65 (1H, dd, J 8 and 8), 8.42 (1H, s), 10.19 (1H, d, J 7); m/z(ES⁺) 350 (M⁺+H).

EXAMPLE 483-(6-Phenylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0355] A degassed solution of 2,6-dibromopyridine (4.0 g, 16.5 mmol) andphenylboronic acid (2.1 g, 16.7 mmol) in dry tetrahydrofuran (30 ml) wasstirred under an atmosphere of nitrogen then sodium carbonate (3.55 g,33.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.95 g, 5 mol%) added. This mixture was heated to reflux for 18 h. After cooling toambient temperature, solvent was removed in vacuo, the residue dissolvedin dichloromethane, washed with water and saturated brine, then driedover magnesium sulfate, filtered and evaporated in vacuo to give asolid. Purification by chromatography on silica gel eluting withdichloromethane gave 2-bromo-6-phenylpyridine (0.17 g) as a white solid:δ_(H) (400 MHz, CDCl₃) 7.45 (4H, m), 7.60 (1H, dd, J 8 and 8), 7.70 (1H,d, J 8), 7.99 (2H, d, J 8); m/z (ES⁺) 233/235 (M⁺+H).

[0356] 2-Bromo-6-phenylpyridine (0.17 g, 0.7 mmol) was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.9 mmol)by the method of Example 1. Purification by chromatography on silica geleluting with dichloromethane on a gradient of methanol (0-10%) andtrituration with ethyl acetate gave3-(6-phenylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (82mg) as a pale yellow solid: δ_(H) (400 MHz, CDCl₃) 7.39 (1H, d, J 7),7.53 (3H, m), 7.70 (1H, d, J 8), 7.78 (1H, d, J 8), 7.91 (1H, dd, J 8and 8), 8.01 (2H, d, J 8), 8.53 (1H, s), 10.62 (1H, d, J 7); m/z (ES⁺)341 (M⁺+H).

EXAMPLE 496-(7-Trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,3′-bipyridine

[0357] 3-Tributylstannylpyridine (3.3 g, 9.0 mmol) was added to adegassed solution of 2,6-dibromopyridine (2.0 g, 8.3 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.48 g, 5 mol %) in drytetrahydrofuran (30 ml), stirred under an atmosphere of nitrogen andheated to reflux for 48 h. After cooling to ambient temperature, solventwas removed in vacuo, the residue dissolved in dichloromethane andpurified by chromatography on silica gel eluting with dichloromethane ona gradient of methanol (04%). Trituration with isohexane gave6-bromo-2,3′-bipyridine (0.4 g) as a solid: δ_(H) (400 MHz, CDCl₃) 7.42(1H, dd, J 8 and 8), 7.49 (1H, d, J 7), 7.65 (1H, dd, J 7 and 7), 7.73(1H, d, J 7), 8.35 (1H, m), 8.68 (1H, m), 9.16 (1H, s); m/z (ES⁺)235/236 (M⁺+H).

[0358] 6-Bromo-2,3′-bipyridine (0.37 g, 1.6 mmol) was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.6 mmol)by the method of Example 1. Purification by chromatography on silica geleluting with dichloromethane on a gradient of methanol (0-5%) andtrituration with isohexane gave6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,3′-bipyridine (130mg) as a pale yellow solid: δ_(H) (400 MHz, CDCl₃) 7.40 (1H, d, J 7),7.50 (1H, dd, J 8 and 8), 7.72 (1H, d, J 8), 7.85 (1H, d, J 8), 7.97(1H, dd, J 8 and 8), 8.30 (1H, m), 8.59 (1H, s), 8.75 (1H, m), 9.29 (1H,s), 10.51 (1H, d, J 7); m/z (ES⁺) 341 (M⁺+H).

EXAMPLE 50N-[6-(7-Trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]acetamide

[0359] Acetyl chloride (0.90 ml, 12.6 mmol) was added dropwise to astirred solution of 2-amino-6-bromopyridine (2.0 g, 11.3 mmol) andtriethylamine (3.2 ml, 23.1 mmol) in dry dichloromethane (15 ml) underan atmosphere of nitrogen at 0° C. After allowing to return to ambienttemperature, solvent was removed in vacuo and the residue purified bychromatography on silica gel eluting with 40% ethyl acetate inisohexane. This gave N-(6-bromopyridin-2-yl)acetamide (0.45 g) as awhite solid: δ_(H) (400 MHz, CDCl₃) 2.19 (3H, s), 7.20 (1H, d, J 8),7.55 (1H, dd, J 9 and 9), 7.90 (1H, s), 8.14 (1H, d, J 9).

[0360] N-(6-Bromopyridin-2-yl)acetamide (0.33 g, 1.56 mmol) was coupledto 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.6mmol) by the method of Example 1. Purification by chromatography onsilica gel eluting with ethyl acetate on a gradient of methanol (0-5%)gaveN-[6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]acetamide(14 mg) as an off-white solid: δ_(H) (400 MHz, DMSO) 2.19 (3H, s), 7.60(1H, d, J 7), 7.85 (1H, d, J 7), 7.92 (1H, dd, J 8 and 8), 7.97 (1H, d,J 8), 8.90 (1H, s), 10.65 (1H, s), 10.75 (1H, d, J 7); m/z (ES⁺) 321(M⁺+H).

EXAMPLE 51N-(tert-Butyl)-6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-ylamine

[0361] A stirred solution of 2,6-dibromopyridine (4.0 g, 16.5 mmol) andtert-butylamine (1.8 ml, 17.2 mmol) in dimethylsulfoxide (10 ml) washeated at 100° C. in a sealed tube for 20 h. After cooling to ambienttemperature the reaction was diluted with water and extracted intodichloromethane. Combined organic extracts were washed with water andsaturated brine then dried over magnesium sulfate, filtered andevaporated in vacuo to give a solid. Purification by chromatography onsilica gel eluting with 20% diethyl ether in isohexane gave6-bromo-N-(tert-butyl)pyridin-2-ylamine (0.4 g) as a solid: δ_(H) (360MHz, CDCl₃) 1.40 (9H, s), 6.34 (1H, d, J 8), 6.66 (1H, d, J 8), 7.18(1H, dd, J 8 and 8); m/z (ES⁺) 229/231 (M⁺+H).

[0362] 6-Bromo-N-(tert-butyl)pyridin-2-ylamine (0.36 g, 1.56 mmol) wascoupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine(1.6 mmol) by the method of Example 1. Purification by chromatography onsilica gel eluting with isohexane on a gradient of ethyl acetate(20-80%) and trituration with isohexane gaveN-(tert-butyl)-6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-ylamine(115 mg) as a pale yellow solid: δ_(H) (400 MHz, CDCl₃) 1.56 (9H, s),7.42 (1H, d, J 7), 7.45 (1H, d, J 8), 7.68 (1H, dd, J 8 and 8), 7.78(1H, d, J 8), 8.53 (1H, s), 10.33 (1H, d, J 7).

EXAMPLE 523-[6-(1H-[1,2,4]Triazol-1-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0363] A stirred solution of 2,6-dibromopyridine (2.0 g, 8.3 mmol) and1,2,4-triazole sodium salt (1.0 g, 9.9 mmol) in dimethylsulfoxide (10ml) was heated at 60° C. for 5 h. After cooling to ambient temperaturethe reaction was diluted with water and extracted into dichloromethane.Combined organic extracts were washed with water and saturated brinethen dried over magnesium sulfate, filtered and evaporated in vacuo togive a solid. Purification by chromatography on silica gel eluting withdichloromethane, then dichloromethane containing 5% methanol, gave2-bromo-6-(1H-[1,2,4]triazol-1-yl)pyridine (0.84 g) as a white solid:δ_(H) (400 MHz, CDCl₃) 7.49 (1H, d, J 8), 7.74 (1H, dd, J 8 and 8), 7.87(1H, d, J 8), 8.09 (1H, s), 9.15 (1H, s); m/z (ES⁺) 224/226 (M⁺+H).

[0364] 2-Bromo-6-(1H-[1,2,4]triazol-1-yl)pyridine (0.25 g, 1.13 mmol)was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.13 mmol)by the method of Example 1. Purification by chromatography on silica geleluting with ethyl acetate on a gradient of methanol (0-10%) andtrituration with ethyl acetate gave3-[6-(1H-[1,2,4]triazol-1-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine(117 mg) as a pale yellow solid: δ_(H) (400 MHz, CDCl₃) 7.44 (1H, d, J7), 7.84 (1H, d, J 8), 7.90 (1H, d, J 8), 8.07 (1H, dd, J 8 and 8), 8.19(1H, s), 8.59 (1H, s), 9.12 (1H, s), 10.16 (1H, d, J 7); m/z (ES⁺) 331(M⁺+H).

EXAMPLE 533-[6-(Isothiazol-4-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-αpyrimidine

[0365] A degassed solution of 4-bromoisothiazole (1.43 g, 8.7 mmol) andbis(neopentyl glycolato)diboron (1.97 g, 8.7 mmol) was reacted as inExample 19 and gave 4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)isothiazole(0.85 g) as an off-white solid: δ_(H) (400 MHz, CDCl₃) 1.03 (6H, s),3.76 (2H, s), 8.74 (1H, s), 9.02 (1H, s); m/z (ES⁺) 130 (M⁺+H).

[0366] A degassed solution of 2,6-dibromopyridine (0.86 g, 3.56 mmol)and 4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)isothiazole (0.35 g, 1.78mmol) in dry 1,4-dioxane (10 ml) was stirred under an atmosphere ofnitrogen, then cesium carbonate (1.20 g, 3.68 mmol) andtetrakis(triphenylphosphine)-palladium(0) (0.10 g, 5 mol %) added. Thismixture was heated to reflux for 18 h. After cooling to ambienttemperature, solvent was removed in vacuo, the residue dissolved indichloromethane, washed with water and saturated brine, then dried overmagnesium sulfate, filtered and evaporated in vacuo to give a solid.Purification by chromatography on silica gel, eluting withdichloromethane on a gradient of methanol (0-5%), gave2-bromo-6-(isothiazol-4-yl)pyridine (0.33 g) as a white solid: δ_(H)(400 MHz, CDCl₃) 7.42 (1H, dd, J 7 and 2), 7.60 (2H, m), 9.01 (1H, s),9.16 (1H, s); m/z (ES⁺) 240/242 (M⁺+H).

[0367] 2-Bromo-6-(isothiazol-4-yl)pyridine (0.27 g, 1.13 mmol) wascoupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine(1.13 mmol) by the method of Example 1. Purification by chromatographyon silica gel eluting with isohexane on a gradient of ethyl acetate(20-80%) and trituration with isohexane gave3-[6-(isothiazol-4-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine(130 mg) as a pale yellow solid: δ_(H) (400 MHz, CDCl₃) 7.41 (1H, d, J7), 7.62 (1H, d, J 8), 7.78 (1H, d, J 8), 7.92 (1H, dd, J 8 and 8), 8.56(1H, s), 9.12 (1H, s), 9.13 (1H, s), 10.45 (1H, d, J 7); m/z (ES⁺) 347(M⁺+H).

EXAMPLE 543-(6-Isopropoxypyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0368] Sodium (0.50 g, 21.7 mmol) was dissolved in isopropanol (50 ml)under an atmosphere of nitrogen with warming at 80° C., then allowed tocool to ambient temperature. 2,6-Dibromopyridine (10.0 g, 41.4 mmol) wasadded and the solution heated to 90° C. After 5 h the cooled reactionmixture was partitioned between diethyl ether (150 ml) and water (100ml). Diethyl ether extracts were washed with water and saturated brinethen dried over magnesium sulphate, filtered and evaporated in vacuo togive a semi-solid. Addition of isohexane, filtration and concentrationin vacuo gave a residue that was purified by chromatography on silicagel eluting with dichloromethane to give 2-bromo-6-isopropoxypyridine(2.1 g) as a colourless liquid: δ_(H) (400 MHz, CDCl₃) 1.33 (6H, d, J6), 5.28 (1H, quin, J 6), 6.60 (1H, d, J 8), 7.00 (1H, d, J 7), 7.38(1H, dd, J 7 and 8); m/z (ES⁺) 214/216 (M⁺+H).

[0369] 2-Bromo-6-isopropoxypyridine (0.32 g, 1.58 mmol) was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.13 mmol)by the method of Example 1. Purification by chromatography on silica geleluting with isohexane on a gradient of ethyl acetate (20-40%) andtrituration with isohexane gave3-(6-isopropoxypyridin-2-yl)-7-(trifluoromethyl)imidazo[1,2-α]pyrimidine(130 mg) as a pale yellow solid: δ_(H) (400 MHz, CDCl₃) 1.45 (6H, d, J6), 5.29 (1H, quin, J 6), 6.69 (1H, d, J 8), 7.34 (1H, d, J 7), 7.39(1H, d, J 7), 7.70 (1H, dd, J 8 and 7), 8.46 (1H, s), 10.26 (1H, d, J7); m/z (ES⁺) 323 (M⁺+H).

EXAMPLE 553-(6-Ethoxypyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0370] Sodium (0.48 g, 20.9 mmol) was dissolved in ethanol (50 ml) underan atmosphere of nitrogen at ambient temperature. 2,6-Dibromopyridine(10.0 g, 41.4 mmol) was added and the solution heated to reflux. After 6h the cooled reaction mixture was partitioned between diethyl ether (150ml) and water (100 ml). Diethyl ether extracts were washed with waterand saturated brine then dried over magnesium sulphate, filtered andevaporated in vacuo to give a semi-solid. Addition of isohexane,filtration and concentration in vacuo gave a residue that was purifiedby chromatography on silica gel eluting with 80%dichloromethane-isohexane to give 2-bromo-6-ethoxypyridine (1.7 g) as acolourless liquid: δ_(H) (400 MHz, CDCl₃) 1.38 (3H, t, J 7), 4.34 (2H,quartet, J 7), 6.65 (1H, d, J 8), 7.02 (1H, d, J 7), 7.40 (1H, dd, J 7and 8); m/z (ES⁺) 202/204 (M⁺+H).

[0371] 2-Bromo-6-ethoxypyridine (0.30 g, 1.48 mmol) was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.13 mmol)by the method of Example 1. Purification by chromatography on silica geleluting with isohexane on a gradient of ethyl acetate (20-40%) andtrituration with isohexane gave3-(6-ethoxypyridin-2-yl)-7-(trifluoromethyl)imidazo[1,2-α]pyrimidine (90mg) as a pale yellow solid: δ_(H) (400 MHz, CDCl₃) 1.50 (3H, t, J 7),4.45 (2H, quartet, J 7), 6.73 (1H, d, J 8), 7.34 (1H, d, J 7), 7.41 (1H,d, J 7), 7.71 (1H, dd, J 8 and 7), 8.46 (1H, s), 10.31 (1H, d, J 7); m/z(ES⁺) 309 (M⁺+H).

EXAMPLE 566-(7-Trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,2′-bipyridine

[0372] 2-Tri-n-butylstannylpyridine (3.80 g, 8.2 mmol) was added to adegassed and stirred solution of 2,6-dibromopyridine (2.00 g, 8.3 mmol)and tetrakis(triphenylphosphine)palladium(0) (5 mol %) intetrahydrofuran (30 ml) under an atmosphere of nitrogen then heated toreflux for 48 h. Solvent was removed in vacuo and purification bychromatography on silica gel eluting with dichloromethane followed bytrituration with isohexane gave 6-bromo-2,2′-bipyridine (0.45 g) as awhite solid: δ_(H) (400 MHz, CDCl₃) 7.31-7.34 (1H, m), 7.49 (1H, d),7.67 (1H, dd), 7.80-7.84 (1H, m), 7.37-8.42 (2H, m), 8.66-8.68 (1H, m);m/z (ES⁺) 234/236 (M⁺+H).

[0373] 6-Bromo-2,2′-bipyridine (0.35 g, 1.44 mmol) was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.13 mmol)by the method of Example 1. Purification by chromatography on silica geleluting with isohexane on a gradient of ethyl acetate (20-100%) andtrituration with isohexane gave6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,2′-bipyridine (130mg) as a pale yellow solid: δ_(H) (400 MHz, CDCl₃) 7.39-7.43 (2H, m),7.85 (1H, d, J 8), 7.89-7.94 (1H, m), 7.99 (1H, dd, J 8 and 8), 8.31(1H, d, J 8), 8.38 (1H, d, J 8), 8.56 (1H, s), 8.75-8.80 (1H, m), 10.53(1H, d, J 7); m/z (ES⁺) 342 (M⁺+H).

EXAMPLE 576-(7-Trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,4′-bipyridine

[0374] 4-Tri-n-butylstannylpyridine (3.30 g, 8.9 mmol) was added to adegassed and stirred solution of 2,6-dibromopyridine (2.00 g, 8.3 mmol)and tetrakis(triphenylphosphine)palladium(0) (5 mol %) intetrahydrofuran (30 ml) under an atmosphere of nitrogen then heated toreflux for 48 h. Solvent was removed in vacuo and purification bychromatography on silica gel eluting with dichloromethane followed bytrituration with isohexane gave 6-bromo-2,4′-bipyridinyl (1.05 g) as awhite solid: δ_(H) (400 MHz, CDCl₃) 7.52-7.57 (1H, m), 7.66-7.70 (1H,m), 7.86 (2H, m), 8.10-8.50 (1H, m), 8.72-8.76 (1H, m), 8.77-8.81 (1H,m); m/z (ES⁺) 234/236 (M⁺+H).

[0375] 6-Bromo-2,4′-bipyridine (0.34 g, 1.44 mmol) was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.13 mmol)by the method of Example 1. Purification by chromatography on silica geleluting with isohexane on a gradient of ethyl acetate (20-100%) andtrituration with isohexane gave6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,4′-bipyridine (180mg) as a pale yellow solid: δ_(H) (400 MHz, CDCl₃) 7.43 (1H, d, J 7),7.77 (1H, d, J 8), 7.88-7.91 (3H, m), 7.98 (1H, dd, J 8 and 8), 8.59(1H, s), 8.80-8.85 (1H, m), 10.51 (1H, d, J 7); m/z (ES⁺) 342 (M⁺+M).

EXAMPLE 583-(6-Methoxymethylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0376] 2-Bromo-6-methoxymethylpyridine (0.27 g, 1.34 mmol; preparedaccording to Shawcross et al. in J. Heterocyclic Chem., 1993, 33(2),563-565) was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.34 mmol)by the method of Example 1. Purification by chromatography on silica geleluting with isohexane on a gradient of ethyl acetate (20-100%) andtrituration with isohexane gave3-(6-methoxymethylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine(15 mg) as a yellow solid: δ_(H) (400 MHz, CDCl) 3.54 (3H, s), 4.68 (2H,s), 7.34 (1H, d, J 7), 7.39 (1H, d, J 7), 7.73 (1H, d, J 7), 7.84 (1H,t, J 7), 8.52 (1H, s), 10.51 (1H, d, J 7); m/z (ES⁺) 309 (M⁺+H).

EXAMPLE 593-[6-(Thien-3-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine

[0377] Tetrakis(triphenylphosphine)palladium(0) (5 mol %) was added to adegassed and stirred mixture of 2,6-dibromopyridine (3.78 g, 15.6 mmol)and thiophene-3-boronic acid (2.20 g, 16.8 mmol) in tetrahydrofuran (40ml) under an atmosphere of nitrogen then heated to reflux for 24 h.Solvent was removed in vacuo and purification by chromatography onsilica gel eluting with a gradient of diethyl ether-isohexane (5-10%)gave 2-bromo-6-(thien-3-yl)pyridine (2.20 g) as a white solid: δ_(H)(400 MHz, CDCl₃) 7.32-7.41 (2H, m), 7.53-7.55 (2H, m), 7.61-7.64 (1H,m), 7.94-7.96 (1H, m); m/z (ES⁺) 240/242 (M⁺+H).

[0378] 2-Bromo-6-(thien-3-yl)pyridine (2.20 g, 9.1 mmol) was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (9.0 mmol)by the method of Example 1. Purification by chromatography on silica geleluting with isohexane on a gradient of ethyl acetate (10-80%) andtrituration with isohexane followed by crystallisation from ethylacetate-isohexane gave3-[6-(thien-3-yl)pyridin-2-yl]-7-trifluoromethyl-imidazo[1,2-α]pyrimidine(350 mg) as a pale yellow solid: δ_(H) (400 MHz, CDCl₃) 7.40 (1H, d, J7), 7.48-7.50 (1H, m), 7.60 (1H, d, J 8), 7.69-7.73 (2H, m), 7.86 (1H,dd, J 8 and 8), 7.92-7.94 (1H, m), 8.54 (1H, s), 10.56 (1H, d, J 7); m/z(ES⁺) 347 (M⁺+H).

EXAMPLE 607-(1,1-Dimethoxyethyl)-3-[2-(pyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine

[0379] Boron trifluoride diethyl etherate (17.03 g, 120.0 mmol) wasadded dropwise over 15 min to a cooled (−40° C.) solution of triethylorthoformate (14.82 g, 100.0 mmol) in dichloromethane (150 ml). Stirringwas continued for 10 min then the solution was transferred to anice-water bath and stirred at 0° C. for 20 min. The mixture was cooledto −78° C. and 3,3-dimethoxybutan-2-one (6.61 g, 50.0 mmol) was addedfollowed by dropwise addition of N,N-diisopropylethylamine (19.39 g,150.0 mmol) over 15 min. After stirring at −78° C. for 15 min thereaction was allowed to reach ambient temperature before pouring theresulting orange solution into a mixture of saturated sodiumhydrogencarbonate solution (500 ml) and dichloromethane (200 ml). Thismixture was vigorously stirred for 15 min, the organic phase wasseparated, washed with ice-cold 1M sulphuric acid solution (2×300 ml),ice-cold water (2×300 ml), dried over anhydrous magnesium sulfate andconcentrated to give crude 1,1-diethoxy-4,4-dimethoxypentan-3-one (14g, >100%) as an orange oil: δ_(H) (360 MHz, CDCl₃) 1.18 (6H, t, J 7),1.36 (3H, s), 2.93 (1H, d, J 6), 3.23 (2H, s), 3.25 (3H, s), 3.51-3.73(4H, m), 5.03 (1H, t, J 6).

[0380] A suspension of sodium methoxide (3.1 g, 57 mmol) and2-aminoimidazole hemisulfate (6.6 g, 50 mmol) in methanol (50 ml) washeated at 80° C. for 30 min before adding a solution of crude1,1-diethoxy-4,4-dimethoxypentan-3-one (14 g) in methanol (50 ml). Thereaction was heated at 80° C. for 12 h, cooled to ambient temperaturethen evaporated to dryness. The residue was suspended in dichloromethaneand the solids removed by filtration. Purification of the filtrate bychromatography on silica gel eluting with dichloromethane (containing 1%conc. ammonia) on a gradient of methanol (1-5%) afforded an orangesolid. Trituration with 20% diethyl ether in isohexane gave7-(1,1-dimethoxyethyl)imidazo[1,2-α]pyrimidine (6.73 g, 65% forsequence) as a cream-coloured solid: δ_(H) (400 MHz, CDCl₃) 1.70 (3H,s), 3.28 (6H, s), 7.30 (1H, d, J 7), 7.55 (1H, d, J 1), 7.84 (1H, d, J1), 8.43 (1H, d, J 7).

[0381] A mixture of 7-(1,1-dimethoxyethyl)imidazo[1,2-α]pyrimidine (5.3g, 26 mmol), potassium bromide (3.1 g, 26 mmol) and sodium acetate (3.2g, 39 mmol) in methanol (50 ml) was cooled to 0° C. before dropwiseaddition of bromine (4.5 g, 28 mmol) over 10 min. After stirring at 0°C. for a further 15 min the reaction was treated with 1M sodium sulphitesolution (5 ml) and the solvent removed in vacuo. The residue wastreated with dichloromethane (100 ml) then saturated sodiumhydrogencarbonate solution (100 ml) was added. After stirring vigorouslyfor 10 min the organic layer was collected, washed with 1M sodiumsulphite solution (100 ml), water, brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. Trituration of the residuewith diethyl ether furnished3-bromo-7-(1,1-dimethoxyethyl)imidazo[1,2-α]pyrimidine (5.05 g, 69%) asa cream-coloured solid: δ_(H) (360 MHz, CDCl₃) 1.70 (3H, s), 3.28 (6H,s), 7.43 (1H, d, J 7), 7.82 (1H, s), 8.39 (1H, d, J 7).

[0382] To a solution of3-bromo-7-(1,1-dimethoxyethyl)imidazo[1,2-α]pyrimidine (1.0 g, 3.5 mmol)at −45° C. was added isopropylmagnesium chloride (2.6 ml of a 2Msolution in THF, 5.2 mmol) dropwise. After stirring at −45° C. for 1.5 htri-n-butylstannyl chloride (1.52 ml, 5.6 mmol) was added dropwise. Thesolution was stirred at −45° C. for 15 min then the cooling bath wasremoved and the solution stirred at room temperature for 1.5 h. Afterthis time half of the solution was taken and degassed with N₂ for 15min. 4-Chloro-2-(pyridin-4-yl)pyrimidine (prepared according to J. Med.Chem., 1982, 25(7), 837-842) (487 mg, 2.55 mmol) andtetrakis(triphenylphosphine)palladium(0) (294 mg, 0.26 mmol) were thenadded and the mixture heated at reflux for 18 h. After this time thesolvent was evaporated and the residue partitioned betweendichloromethane (2×40 ml) and water (40 ml). The combined organic layerswere washed with brine (40 ml), dried (MgSO₄) and evaporated. Theresidue was chromatographed on silica gel, eluting with 1:1isohexane:ethyl acetate followed by dichloromethane:MeOH (97:3), toafford7-(1,1-dimethoxyethyl)-3-[2-(pyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine(171 mg, 28%) as an off-white solid: δ_(H) (360 MHz, CDCl₃) 1.76 (3H,s), 3.33 (6H, s), 7.66-7.69 (2H, m), 8.28 (2H, dd, J 4.6 and 1.5), 8.60(1H, s), 8.80-8.90 (3H, m), 10.30 (1H, d, J 7.3); m/z (ES+) 363 (M⁺+H).

EXAMPLE 612-{3-[2-(3-Nitrophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol

[0383] A mixture of3-(2-chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine(prepared according to Example 34) (250 mg, 0.62 mmol),3-nitrobenzeneboronic acid (207 mg, 1.24 mmol) andtetrakis(triphenylphosphine)palladium(0) (71 mg, 10 mol %) in THF (3 ml)and 2N Na₂CO₃ solution (1.24 ml, 2.48 mnmol) was heated at reflux for2.5 h. The mixture was cooled to room temperature, diluted with CH₂Cl₂(30 ml), separated and concentrated to approximately 2 ml under reducedpressure. Purification by column chromatography on silica using 3%MeOH/CH₂Cl₂ afforded7-(1-methyl-1-triethylsilanyloxyethyl)-3-[2-(3-nitrophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine:m/z (ES+) 491 (M⁺H+).

[0384]7-(1-Methyl-1-triethylsilanyloxyethyl)-3-[2-(3-nitrophenyl)-pyrimidin-4-yl]imidazo[1,2-α]pyrimidinein EtOH (10 ml) was treated with conc. HCl (10 drops) and stirred atroom temperature for 12 h. The crude mixture was poured onto an SCXcartridge (2 gram) and washed firstly with MeOH (20 ml) to remove theimpurities and then 2N NH₃ in MeOH (20 ml) to elute the desiredcompound. Removal of the solvent under reduced pressure afforded2-{3-[2-(3-nitrophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol(66 mg, 28%): ¹H NMR (360 MHz, CDCl₃) δ 10.31 (1H, d, J 7.3), 9.31 (1H,t, J 1.8), 8.83 (1H, d, J 5.5), 8.80 (1H, d, J 8.0), 8.55 (1H, s), 8.40(1H, d, J 8.0), 7.75 (1H, t, J 8.0), 7.66 (1H, d, J 5.5), 7.40 (1H, d, J7.3), 1.68 (6H, s); m/z (ES⁺) 377 (M+H⁺).

EXAMPLE 622-{3-[2-(3-Fluorophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol

[0385]3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidine(250 mg, 0.62 mmol) and 3-fluorobenzene-boronic acid (173 mg, 1.24 mmol)were reacted as described in Example 61. Purification by columnchromatography on silica using 3% MeOH/CH₂Cl₂ gave3-[2-(3-fluorophenyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine:m/z (ES⁺) 464 (M+H⁺).

[0386] The foregoing compound was deprotected as described in Example 61and purified on an SCX cartridge to afford2-{3-[2-(3-fluorophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol(141 mg, 65%): ¹H NMR (360 MHz, d⁶-DMSO) δ 10.19 (1H, d, J 7.3), 8.92(1H, d, J 5.5), 8.83 (1H, s), 8.32 (1H, d, J 7.9), 8.15 (1H, dt, J 10.4,1.6), 8.03 (1H, d, J 5.5), 7.76 (1H, d, J 7.3), 7.68-7.60 (1H, m),7.47-7.38 (1H, m), 5.61 (1H, s), 1.55 (6H, s); m/z (ES⁺) 350 (M+H⁺).

EXAMPLE 631-[3-(2-(Pyridin-4-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]ethanone

[0387] A solution of7-(1,1-dimethoxyethyl)-3-[2-(pyridin-4yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine(Example 60) (3 g, 8.3 mmol) in 2.5N HCl (60 ml) was heated at 50° C.for 4 h. To the cooled solution was added 5% MeOH/DCM (500 ml) thenneutralized by portionwise addition of a saturated solution of NaHCO₃.Organic layer was separated and the aqueous re-extracted twice with 5%MeOH/DCM. Combined organics washed with brine, dried (MgSO₄) andconcentrated in vacuo to give the crude residue. The crude was purifiedusing 100 g silica bond elute cartridge, eluting with 1-2.5% MeOH/DCM,to afford1-[3-(2-(pyridin-4-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]ethanoneas a yellow solid (1.6 g, 61%): ¹H NMR (400 MHz, d⁶DMSO) δ 2.74 (3H, s),7.92 (1H, d, J 7.2), 8.23 (1H, d, J 5.5), 8.37 (2H, dd, J 1.6, 4.3),8.83 (2H, dd, J 1.6, 4.3), 9.04 (1H, d, J 5.5), 9.15 (1H, s), 10.39 (1H,d, J 7.4); m/z (ES⁺) 317 (M+H⁺).

EXAMPLE 646-[7-([1,2,4]Triazol-1-ylmethyl)imidazo[1,2-α]pyrimidinyl-3-yl]-2,3′-bipyridinedihydrochloride

[0388] Pyruvic aldehyde dimethyl acetal (8.43 g, 71.4 mmol) andN,N-dimethylformamide dimethyl acetal (8.51 g, 71.4 mmol) were heated at100° C. for 18 h. The mixture was concentrated to give a brown oil andwas then added dropwise over 10 min to a warm (60° C.) suspension of2-aminoimidazole hemisulfate (9.43 g, 71.4 mmol) in water (50 ml). Themixture was heated at 50° C. for 36 h, cooled to ambient temperature andthen pre-adsorbed directly onto silica. Purification by chromatographyon silica gel eluting with dichloromethane (containing 1% conc. ammonia)on a gradient of methanol (1-2%) gave a 3:1 mixture of7-dimethoxymethyl-imidazo[1,2-α]pyrimidine and5-dimethoxymethylimidazo[1,2-α]pyrimidine respectively. Crystallisationfrom toluene gave 7-dimethoxymethylimidazo[1,2-α]pyrimidine (2.20 g,16%) as a brown crystalline solid: δ_(H) (400 MHz, CDCl₃) 3.50 (6H, s),5.26 (1H, s), 7.15 (1H, d, J 7), 7.56 (1H, d, J 1), 7.84 (1H, d, J 1),8.47 (1H, d, J 7).

[0389] 7-Dimethoxymethylimidazo[1,2-α]pyrimidine (1.00 g, 5.18 mmol) wasdissolved in 3N hydrochloric acid and heated at 48° C. for 14 h. Thesolution was layered with ethyl acetate (30 ml) and solid sodiumhydrogencarbonate (1.06 g, 12.6 mmol) was added in portions over 5 min.The mixture was diluted with water (6 ml) and extracted withdichloromethane (5×50 ml). The combined organics were dried overanhydrous sodium sulfate, filtered and evaporated to giveimidazo[1,2-α]pyrimidine-7-carbaldehyde (749 mg, 99%) as a yellow solid:δ_(H) (360 MHz, CDCl₃) 7.53 (1H, d, J 7), 7.77 (1H, d, J 1), 8.10 (1H,d, J 1), 8.60 (1H, d, J 7), 10.05 (1H, s).

[0390] Sodium triacetoxyborohydride (21.5 g, 102 mmol) was addedportionwise over 20 min to a stirred solution ofimidazo[1,2-α]pyrimidine-7-carbaldehyde (5.00 g, 34.0 mmol) in methanol(100 ml) and the solution left to stir at ambient temperature for 18 h.The solvent was evaporated, the residue redissolved in methanol (150 ml)and pre-adsorbed onto silica. Purification by chromatography on silicagel eluting with dichloromethane (containing 1% conc. ammonia) on agradient of methanol (1-10%) gave imidazo[1,2-α]pyrimidin-7-ylmethanol(5.06 g, 99%) as a white solid: δ_(H) (360 MHz, DMSO) 4.57 (2H, d, J 6),5.62 (1H, t, J 6), 7.13 (1H, d, J 7), 7.64 (1H, d, J 1), 7.86 (1H, d, J1), 8.94 (1H, d, J 7).

[0391] To a solution of imidazo[1,2-α]pyrimidin-7-ylmethanol (4.64 g,34.1 mmol) in dichloromethane under an atmosphere of nitrogen was addedtriphenylphosphine (10.6 g, 40.5 mmol) and carbon tetrabromide (13.4 g,40.5 mmol). This mixture was stirred at room temperature for 2.5 hbefore addition of ethereal hydrogen chloride (1.0M, 100 ml) in adropwise manner and allowed to stir at room temperature for a further 1h. Reaction mixture was evaporated to dryness under reduced pressure andthe resulting solid washed with dichloromethane followed by ether andthen dried under vacuum to give 7-chloromethylimidazo[1,2-α]pyrimidinehydrochloride salt (5.0 g, 79%) as a pale brown solid: δ_(H) (360 MHz,d⁶-DMSO) 5.06 (2H, s), 7.77 (1H, d, J 7), 8.31-8.35 (2H, m), 9.37 (1H,d, J 7); m/z (ES⁺) 168, 170 (M⁺+H).

[0392] To a solution of 1H-[1,2,4]triazole (2.2 g, 31.9 mmol) inanhydrous N,N-dimethylformamide (20 ml) under a nitrogen atmosphere wasadded sodium hydride (1.18 g, 29.4 mmol, 60% dispersion in oil) withcaution in a portionwise manner. This mixture was then stirred for 20min at room temperature. To a separate solution of7-chloromethylimidazo[1,2-α]pyrimidine hydrochloride (5.0 g, 24.5 mmol),also dissolved in N,N-dimethylformamide (50 ml) under nitrogen, wasadded potassium carbonate (6.76 g, 49.0 mmol) and the mixture stirredfor 5 min at room temperature. To the7-chloromethylimidazo[1,2-α]pyrimidine solution was added the triazolesodium salt as a solution in N,N-dimethylformamide and the mixturestirred at room temperature for 16 h. Solvent was removed under reducedpressure and the resulting residue purified by flash columnchromatography on silica eluting with dichloromethene, methanol andaqueous ammonia solution (33%) in the ratios 90:5:0.5 respectively togive 7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-α]pyrimidine (3.38 g, 69%)as a tan solid: δ_(H) (360 Mz, d⁶-DMSO) 5.63 (2H, s), 6.90 (1H, d, J 7),7.71 (1H, d, J 1.3), 7.91 (1H, d, J 1.4), 8.04 (1H, s), 8.73 (1H, s),8.97 (1H, d, J 7); m/z (ES⁺) 201 (M⁺+H).

[0393] To 7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-α]pyrimidine (3.38 g,16.9 mmol) in methanol (300 ml) saturated with potassium bromide wasadded sodium acetate (4.16 g, 50.7 mmol). This mixture was cooled (−10°C.) and bromine (2.70 g, 16.9 mmol) added dropwise over a five minuteperiod. Stirring at this temperature was continued for 15 min beforequenching the reaction with 5% (w/v) sodium sulphite solution (20 ml).Mixture was stirred for 15 min and methanol removed under reducedpressure. Residue was partitioned between dichloromethane (100 ml) andsaturated sodium hydrogencarbonate solution (100 ml). Product wasextracted into dichloromethane (4×100 ml) then the combined organicextracts were washed with brine (300 ml) and dried over anhydrousmagnesium sulphate. Drying agent was removed by filtration and filtratedried under reduced pressure to give3-bromo-7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-α]pyrimidine (4.60 g,97%) as a pale yellow solid: δ_(H) (360 MHz, d₆-DMSO) 5.69 (2H, s), 7.06(1H, d, J 7), 7.88 (1H, s), 8.05 (1H, s), 8.74 (1H, s), 8.80 (1H, d, J7); m/z (ES⁺) 279, 281 (M⁺+H).

[0394] To a cooled (−78° C.) solution of3-bromo-7-([1,2,4]triazol-1-ylmethyl)-imidazo[1,2-α]pyrimidine (0.42 g,1.50 mmol) in tetrahydrofuran (15 ml) was added isopropylmagnesiumchloride (0.82 ml of a 2M solution in tetrahydrofuran, 2.37 mmol).Mixture was allowed to warm to −45° C. and stirring at this temperaturewas continued for 0.5 h. Mixture was recooled to −78° C., tributyltinchloride (0.47 ml, 1.72 mmol) added in a dropwise fashion, stirred for10 min at −78° C. and then allowed to warm to ambient temperature. Thisprocess of Grignard formation with subsequent transmetallation to thestannane intermediate was repeated to encourage completion of thereaction giving7-([1,2,4]triazol-1-ylmethyl)-3-tributylstannylimidazo[1,2-α]pyrimidineas a solution in tetrahydrofuran (ca. 0.1M); m/z (ES⁺) 487, 489, 490(M⁺+H).

[0395] To the degassed solution of7-([1,2,4]triazol-1-ylmethyl)-3-tributylstannylimidazo[1,2-α]pyrimidinewas added 6-bromo-2,3′-bipyridine (prepared according to Example 49)(0.39 g, 1.65 mmol) and tetrakis(triphenylphosphine)palladium(0) (173mg, 0.10 mmol) and the mixture heated at reflux for 3 h. The crudereaction was adsorbed onto silica and purified by chromatography onsilica gel eluting with a dichloromethane, methanol, aqueous ammonia(33%) mixture in the volume ratios of 90:5:0.5 respectively to give6-[7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-α]pyrimidin-3-yl]-2,3′-bipyridineas a hygroscopic solid following crystallisation fromdichloromethane/ethyl acetate. Addition of an excess of 1M HCl in etherto a solution of the product in a methanol/ether solvent mixture gave 50mg of the dihydrochloride salt as a white solid: δ_(H) (360 MHz, CDCl₃)5.62 (2H, s), 6.96 (1H, d, J 7), 7.47 (1H, dd, J 4.7 and 4.7), 7.66 (1H,d, J 7.7), 7.78 (1H, d, J 7.9), 7.91 (1H, t, J 9), 8.05 (1H, s),8.23-8.27 (1H, m), 8.36 (1H, s), 8.41 (1H, s), 8.71-8.72 (1H, m), 9.25(1H, 8), 10.30 (1H, d, J 7.2); m/z (ES⁺) 355 (M⁺+H).

EXAMPLE 652-[6-(7-([1,2,4]Triazol-1-ylmethyl)imidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]benzonitriletrifluoroacetate

[0396] 3-Bromo-7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-α]pyrimidine(0.2 g, 0.72 mmol) was coupled to 2-(6-bromopyridin-2-yl)benzonitrile(prepared according to Example 27) following the procedure in Example 64and purified by LC/MS to give2-[6-(7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]benzonitriletrifluoroacetate as a white solid: δ_(H) (400 MHz, CDCl₃) 5.67 (2H, s),7.26 (1H, d, J 7.2), 7.60-7.67 (2H, m), 7.75 (1H, dd, J 8, 7 and 1),7.89-8.04 (3H, m), 8.10 (1H, s), 8.50 (1H, bs), 8.60 (1H, bs), 10.56(1H, s); m/z (ES⁺) 379 (M⁺+H).

EXAMPLE 666′-(7-Trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,2′-bipyridinyl-3-carbonitrile

[0397] To a degassed solution of 2-chloro-6-tributylstannylpyridine(prepared according to S. Choppin et al. in Org. Lett., 2000, 2, 803-5)(600 mg, 1.49 mmol) and 2-chloro-3-cyanopyridine (412 mg, 2.98 mmol) inTHF was added tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05mmol) and the mixture heated at reflux for 96 hours. The solvent wasremoved under reduced pressure and the crude product chromatographed onsilica, on a gradient of dichloromethane to 2% methanol indichloromethane, to afford 6′-chloro-2,2′-bipyridinyl-3-carbonitrile asa white solid (231 mg): δ_(H) (400 MHz, d⁶-DMSO) 7.71-7.74 (2H, m), 8.11(1H, t, J 7.8), 8.20-8.23 (1H, m), 8.48 (1H, dd, J 1.8, 8.0), 8.97 (1H,dd, J 1.8, 4.9); m/z (ES⁺) 216, 218 (M⁺+H).

[0398] The foregoing compound was coupled to3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine by themethod of Example 1 to give6′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,2′-bipyridinyl-3-carbonitrile:δ_(H) (400 MHz, CDCl₃) 7.40-7.57 (2H, m), 7.99-8.08 (2H, m), 8.16-8.18(1H, m), 8.25 (1H, dd, J 2.0, 7.8), 8.59 (1H, s), 8.96 (1H, dd, J 1.8,4.9), 10.61 (1H, d, J 7.4); m/z (ES⁺) 367 (M⁺+H).

EXAMPLE 676′-[7-(1-Fluoro-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]-2,2′-bipyridinyl-3-carbonitrile

[0399] 6′-Chloro-2,2′-bipyridinyl-3-carbonitrile was coupled to7-(1-fluoro-1-methylethyl)-3-tributylstannylimidazo[1,2-α]pyrimidine(prepared according to Example 25) by the method of Example 1 to give6′-[7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl)-2,2′-bipyridinyl-3-carbonitrile:δ_(H) (400 MHz, CDCl₃) 1.78 (3H, s), 1.84 (3H, s), 7.42 (1H, dd, J 2.0,7.0), 7.55 (1H, dd, J 4.7, 7.8), 7.95 (1H, d, J 1.2), 7.99 (1H, t, J7.8), 8.06-8.08 (1H, m), 8.24 (1H, dd, J 1.6, 7.8), 8.39 (1H, s), 8.94(1H, dd, J 1.6, 4.7), 10.36 (1H, d, J 7.0); m/z 359 (M⁺+H).

EXAMPLES 68 TO 109

[0400] The following compounds were made by methods analogous to thosedescribed above. Example No. Z

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EXAMPLE 1102-{3-[2-(2,4-Difluorophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol

[0401]3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidine(250 mg, 0.62 mmol) and 2,4-difluorobenzeneboronic acid (196 mg, 1.24mmol) were reacted together as described in Example 61. Purification bycolumn chromatography on silica using 2.5% MeOH/CH₂Cl₂ gave3-[2-(2,4-difluorophenyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine:m/z (ES⁺) 482 (M+H⁺).

[0402] The foregoing compound was deprotected as described in Example61, Step 2 and purified on an SCX cartridge to afford2-{3-[2-(2,4-difluorophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl)propan-2-ol(72 mg, 32%): ¹H NMR (360 MHz, CDCl₃) δ 10.19 (1H, d, J 7.2), 8.92 (1H,d, J 5.4), 8.52 (1H, s), 8.30-8.21 (1H, m), 7.60 (1H, d, J 5.4), 7.29(1H, d, J 7.2), 7.10-6.95 (2H, m), 1.65 (6H, s); m/z (ES⁺) 368 (M+H⁺).

EXAMPLE 1112-{3-[2-(3,4-Difluorophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol

[0403]3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo-[1,2-α]pyrimidine(250 mg, 0.62 mmol) and 3,4-difluorobenzeneboronic acid (196 mg, 1.24mmol) were reacted together as described in Example 61. Purification bycolumn chromatography on silica using 2.5% MeOH/CH₂Cl₂ gave3-[2-(3,4-difluorophenyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine:m/z (ES⁺) 482 (M+H⁺).

[0404]3-[2-(3,4-Difluorophenyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidinein EtOH (8 ml) was treated with conc. HCl (15 drops) and stirred at roomtemperature for 12 h. The resulting solid was filtered off and driedunder reduced pressure. The resulting solid was added to a mixture of 1NNaOH (30 ml) and CH₂Cl₂ and stirred vigorously for 5 min. The organicswere separated and the aqueous fraction extracted with CH₂Cl₂ (3×20 ml).The combined organic extracts were dried (MgSO₄) and concentrated underreduced pressure to yield2-{3-[2-(3,4-difluorophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol(74 mg, 33%): ¹H NMR (400 MHz, d⁶-DMSO) δ 10.16 (1H, d, J 7.3), 8.90(1H, d, J 5.5), 8.82 (1H, s), 8.40-8.30 (2H, m), 8.03 (1H, d, J 5.5),7.73 (1H, d, J 7.3), 7.17-7.08 (1H, m), 7.61 (1H, s), 1.55 (6H, s).

EXAMPLE 1122-{3-[2-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol

[0405] Benzyl chloride (460 μl, 4.0 mmol) was added to a stirredsuspension of 4-chloro-2-(pyridin-4-yl)pyrimidine (prepared according toJ. Med. Chem., 1982, 25(7), 837-842) (383 mg, 2.00 mmol) in MeCN (10 ml)and the mixture was heated at reflux for 30 h and then concentratedunder reduced pressure. EtOH (5 ml) was then added, followed by NaBH₄(151 mg, 4.0 mmol), and the mixture stirred at room temperature for 30min. Water (10 ml) and EtOAc (70 ml) were added, separated and theorganics washed with H₂O (20 ml), brine (20 ml) and concentrated underreduced pressure. The residue was purified by column chromatography onsilica using 3% MeOH/CH₂Cl₂ as eluent to yield2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-4-chloropyrimidine (325 mg,57%): ¹H NMR (360 MHz, CDCl₃) δ 8.52 (1H, d, J 5.3), 7.40-7.23 (6H, m),7.11 (1H, d, J 5.3), 3.66 (2H, s), 3.30-3.20 (2H, m), 2.80-2.63 (4H, m);m/z (ES⁺) 286, 288 (1:1, M+H⁺).

[0406]3-Bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine(287 mg, 0.77 mmol) and2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-4-chloropyrimidine: (266 mg,0.93 mmol) were reacted together as described in Example 39, Step 1.Purification by column chromatography on silica, using 4-7.5%MeOH/CH₂Cl₂, gave3-[2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine:m/z (ES⁺) 540 (M+H⁺).

[0407] The foregoing compound was deprotected as described in Example61, Step 2 and purified on an SCX cartridge, followed by columnchromatography on silica, using 10% MeOH/CH₂Cl₂ as eluent, to afford2-{3-[2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol(20 mg, 6%): ¹H NMR (360 MHz, CDCl₃) δ 10.24 (1H, d, J 7.3), 8.68 (1H,d, J 5.4), 8.44 (1H, s), 7.48-7.20 (8H, m), 3.70 (2H, s), 3.38-3.30 (2H,m), 2.85-2.75 (4H, m), 1.66 (6H, s); m/z (ES⁺) 427 (M+H⁺).

EXAMPLE 1132-{3-[2-(1,1-Difluoroethyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol

[0408] A solution of isopropylmagnesium chloride (4.2 mmol) in THF(2.0M, 2.1 ml) was added dropwise to a stirred solution of2-iodo-4-methoxypyrimidine (prepared according to Leprete et al. inTetrahedron, 2000, 56, 265-273) (1.0 g, 4.2 mmol) in THF (12 ml) at 0°C. under N₂. The reaction was stirred for 30 min at 0° C. and then DMA(409 μl, 4.4 mmol) was added. The reaction was stirred for 1 h and thenquenched by addition of NH₄Cl solution (15 ml) and extracted with EtOAc(50 ml and 20 ml). The combined organics were concentrated under reducedpressure and purified by column chromatography on silica, using 75%Et2O/iso-hexanes as eluent, to yield 1-(4-methoxypyrimidin-2-yl)ethanone(206 mg, 32%): ¹H NMR (360 MHz, CDCl₃) δ 8.59 (1H, d, J 5.7), 6.83 (1H,d, J 5.7), 4.08 (3H, s), 2.74 (3H, s); m/z (ES⁺) 153 (M⁺).

[0409] The foregoing compound (505 mg, 3.3 mmol) in 1,2-dichloroethane(20 ml) was treated with [bis(2-methoxyethyl)amino]sulfur trifluoride(1.66 ml, 9.9 mmol) and the reaction mixture was heated at refluxovernight. The mixture was poured into ice (50 ml) and neutralised byaddition of NaHCO₃. The organic products were extracted with CH₂Cl₂(2×30 ml) and then concentrated under reduced pressure. The cruderesidue was purified by column chromatography on silica, using 40%Et₂O/isohexanes as eluent, to yield2-(1,1-difluoroethyl)-4-methoxypyrimidine (271 mg, 47%): ¹H NMR (400MHz, CDCl₃) δ 8.61 (1H, d, J 5.7), 6.77 (1H, d, J 5.7), 4.01 (3H, s),2.04 (3H, t, J 18.5); m/z (ES⁺) 175 (M+H⁺).

[0410] The forementioned compound was heated in the presence of 5N HCl(15 ml) at reflux for 12 h and then concentrated under reduced pressureand dried under reduced pressure to yield2-(1,1-difluoroethyl)pyrimidin-4-ol: ¹H NMR (400 MHz, d⁶-DMSO) δ 8.51(1H, d, J 6.2), 6.65 (1H, d, J 6.2), 1.96 (3H, t, J 19.2).

[0411] The crude pyrimidinol (230 mg, 1.43 mmol) in 1,2-dichloroethane(10 ml) was heated at reflux in the presence of POCl₃ (669 μl, 7.2 mmol)for 16 h. Ice (20 ml) was added, the organics were extracted with CH₂Cl₂(3×50 ml) and then concentrated under reduced pressure to yield4-chloro-2-(1,1-difluoroethyl)pyrimidine (209 mg, 82%): ¹H NMR (400 MHz,CDCl₃) δ 8.72 (1H, d, J 5.2), 7.45 (1H, d, J 5.2), 2.06 (3H, t, J 18.5);m/z (ES⁺) 179, 181 (3:1, M+H⁺).

[0412]3-Bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine(567 mg, 1.4 mmol) and 4-chloro-2-(1,1-difluoroethyl)pyrimidine (209 mg,1.17 mmol) were reacted together as described in Example 39, Step 1.Purification by column chromatography on silica using 3% MeOH/CH₂Cl₂gave3-[2-(1,1-difluoroethyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine.

[0413] The foregoing compound in EtOH (8 ml) was treated with conc. HCl(15 drops) and stirred at room temperature for 4 h. The resultingmixture was poured onto an SCX cartridge (5 g) and washed firstly withMeOH to remove the impurities and then 2N NH₃ in MeOH to elute thedesired compound. The fractions containing the desired material wereconcentrated under reduced pressure while dry loading onto MgSO₄. Theresidue was purified by column chromatography on silica, using 7%MeOH/dichloromethane containing 1% NH₃ solution as eluent, and then bypreparative HPLC using 15-40% MeCN/[0.1% TFA/H₂O], to yield2-{3-[2-(1,1-difluoroethyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol(37 mg, 8%): ¹H NMR (400 MHz, d⁶-DMSO) δ 10.05 (1H, d, J 7.2), 8.92 (1H,d, J 5.5), 8.90 (1H, s), 8.20 (1H, d, J 5.5), 7.71 (1H, d, J 7.2), 5.60(1H, s), 2.13 (3H, t, J 19.1), 1.53 (6H, s); m/z (ES⁺) 320 (M+H⁺).

EXAMPLE 1141-{4-[7-(1-Hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}ethanone

[0414]3-Bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine(5.0 g, 13.5 mmol) and 2,4-diiodopyrimidine (prepared according toLeprete et al. in Tetrahedron, 2000, 56, 265-273) (5.6 g, 16.9 mmol)were reacted together as described in Example 39, Step 1. Purificationby column chromatography on silica using 2.5% MeOH/CH₂Cl₂ gave3-(2-iodopyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine(4.97 g, 74%): ¹H NMR (400 MHz, CDCl₃) δ 9.95 (1H, d, J 7.3), 8.47 (1H,s), 8.35 (1H, d, J 5.4), 7.66 (1H, d, J 7.3), 7.59 (1H, d, J 5.4), 1.66(6H, s), 1.00 (9H, t, J 8.0), 0.67 (6H, q, J 8.0).

[0415] A solution of isopropylmagnesium chloride (10.8 mmol) in THF(2.0M, 5.4 ml) was added dropwise to a stirred solution of theforementioned compound (2.68 g, 5.4 mmol) in THF (70 ml) at −78° C.under N₂. The reaction was stirred for 30 min at −78° C. and thenethanal (665 μl, 11.9 mmol) was added. The reaction was warmed to roomtemperature, stirred for a further 30 min and then quenched by theaddition of NH₄Cl solution (30 ml). The organics were extracted withEtOAc (3×50 ml), then concentrated under reduced pressure while dryloading onto MgSO₄. The residue was purified by column chromatography onsilica, using 6% EtOH/EtOAc as eluent, to yield1-{4-[7-(1-methyl-1-triethylsilanyl-oxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}ethanol(930 mg, 42%): ¹H NMR (400 MHz, CDCl₃) δ 10.10 (1H, d, J 7.2), 8.67 (1H,d, J 5.5), 8.48 (1H, s), 7.61 (1H, d, J 7.2), 7.55 (1H, d, J 5.5), 5.03(1H, quintet, J 5.1), 4.07 (1H, d, J 5.1), 1.62-1.55 (9H, m), 0.99 (9H,t, J 7.8), 0.67 (6H, q, J 7.8); m/z (ES⁺) 414 (M+H⁺).

[0416] Dess-Martin periodinane (1.02 g, 2.4 mmol) was added to a stirredsolution of the above alcohol (500 mg, 1.2 mmol) in CH₂Cl₂ (20 ml) andthe reaction was stirred for 3 h. Further CH₂Cl₂ (50 ml) was added andthen washed with 2N NaOH (50 ml) and brine (30 ml). The organics wereconcentrated under reduced pressure and purified by columnchromatography on silica, using 3% MeOH/CH₂Cl₂ as eluent, to yield1-{4-[7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}ethanone(320 mg, 64%): ¹H NMR (360 MHz, CDCl₃) δ 10.33 (1H, d, J 7.2), 8.82 (1H,d, J 5.5), 8.53 (1H, s), 7.74 (1H, d, J 5.5), 7.67 (1H, d, J 7.2), 2.85(3H, s), 1.70 (6H, s), 1.58 (6H, m), 0.99 (9H, t, J 7.8), 0.67 (6H, q, J7.8); m/z (ES⁺) 411 (M+H⁺).

[0417] The foregoing compound (114 mg, 0.28 mmol) was deprotected asdescribed in Example 61, Step 2 to yield after chromatography on silica,using 12-14% EtOH/EtOAc as eluent,1-{4-[7-(1-hydroxy-1-methylethyl)-imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}ethanone(20 mg, 24%): ¹H NMR (400 MHz, CDCl₃) δ 10.43 (1H, d, J 7.3), 8.84 (1H,d, J 5.4), 8.55 (1H, s), 7.77 (1H, d, J 5.4), 7.36 (1H, d, J 7.3), 5.59(1H, s), 2.84 (3H, s), 1.66 (6H, s); m/z (ES⁺) 298 (M+H⁺).

EXAMPLE 1152-{3-[2-(1-Hydroxy-1-methylethyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol

[0418] A solution of methylmagnesium chloride (1.65 mmol) in THF (3.0 M,550 μl) was added dropwise to a stirred solution of1-{4-[7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}ethanone(Example 114, Step 3) (452 mg, 1.1 mmol) in THF (10 ml) at −78° C. underN₂. The reaction was stirred overnight slowly warming to roomtemperature and then quenched by the addition of NH₄Cl solution (30 ml).The organics were extracted with EtOAc (3×50 ml), then concentratedunder reduced pressure while dry loading onto MgSO₄. The residue waspurified by column chromatography on silica, using 6% ^(i)PrOH/EtOAc aseluent, to yield2-{4-[7-(1-methyl-1-triethylsilanyl-oxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}propan-2-ol(330 mg, 70%): ¹H NMR (400 MHz, CDCl₃) δ 10.05 (1H, d, J 7.3), 8.67 (1H,d, J 5.5), 8.48 (1H, s), 7.61 (1H, d, J 7.2), 7.55 (1H, d, J 5.5),4.10-3.97 (2H, m), 1.21 (6H, s), 1.20 (6H, s), 0.99 (9H, t, J 7.9), 0.67(6H, q, J 7.9); m/z (ES⁺) 428 (M+H⁺).

[0419] The foregoing compound (65 mg, 0.15 mmol) in EtOH (15 ml) wastreated with conc. HCl (10 drops) and stirred at room temperature for 6h. The resulting mixture was concentrated under reduced pressure andthen dissolved in DMSO (4 ml) and purified by preparative HPLC using10-20% MeCN/[0.1% TFA/H₂O]. The MeCN was removed under reduced pressureand NaHCO₃ solution (50 ml) added. The organics were extracted withCH₂Cl₂ (2×100 ml), dried (MgSO₄) and concentrated to yield2-{3-[2-(1-hydroxy-1-methylethyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol(20 mg, 42%): ¹H NMR (360 MHz, CDCl₃) δ 10.16 (1H, d, J 7.3), 8.70 (1H,d, J 5.5), 8.51 (1H, s), 7.57 (1H, d, J 5.5), 7.32 (1H, d, J 7.3), 4.56(1H, s), 4.24 (1H, s), 1.69 (6H, s), 1.66 (6H, s); m/z (ES⁺) 314 (M+H⁺).

EXAMPLE 1162-{3-[2-(1-Fluoro-1-methylethyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol

[0420] (Diethylamino)sulphur trifluoride (150 mg, 0.95 mmol) was addedto a stirred solution of2-{4-[7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}propan-2-ol(Example 115, Step 1) (200 mg, 0.47 mmol) in 1,2-dichloroethane (5 ml)at room temperature under N₂ and the reaction was stirred overnight.Water (20 ml) was added followed by NaHCO₃ solution (20 ml) and then theorganics were extracted with CH₂Cl₂ (3×50 ml) and concentrated underreduced pressure. The residue was purified by column chromatography onsilica using 7% EtOH/EtOAc to yield3-[2-(1-fluoro-1-methylethyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine(60 mg, 30%): ¹H NMR (400 MHz, CDCl₃) δ 10.25 (1H, d, J 7.3), 8.71 (1H,d, J 5.5), 8.48 (1H, s), 7.60 (1H, d, J 7.2), 7.55 (1H, d, J 5.5), 1.87(6H, d, J 21.6), 0.99 (9H, t, J 8.0), 0.68 (6H, q, J 8.0); m/z (ES⁺) 430(M+H⁺).

[0421]3-[2-(1-Fluoro-1-methylethyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine(60 mg, 0.14 mmol) was deprotected as described in Example 61, Step 2 toyield after chromatography on silica, using 6-12% MeOH/(CH₂Cl₂ aseluent,2-{3-[2-(1-fluoro-1-methylethyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol(27 mg, 61%): ¹H NMR (400 MHz, d⁶-DMSO) δ 10.14 (1H, d, J 7.1),8.85-8.75 (2H, m), 8.03 (1H, d, J 5.3), 7.68 (1H, d, J 7.1), 7.55 (1H,d, J 5.5), 5.59 (1H, s), 1.83 (6H, d, J 21.6), 1.54 (6H, s); m/z (ES⁺)316 (M+H⁺).

EXAMPLE 1172-[3-(2-Isopropylpyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol

[0422] A mixture of 2-(imidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (Example21, Step 3) (339 mg, 1.9 mmol), 4-chloro-2-isopropylpyrimidine (300 mg,1.9 mmol), Cs₂CO₃ (1.25 g, 3.8 mmol) andtetrakis(triphenylphosphine)-palladium(0) (221 mg, 10 mol %) in1,4-dioxane (10 ml) was heated at 100° C. under N₂ for 18 h. Water (75ml) was added and the organic products were extracted with CH₂Cl₂ (3×50ml). The combined organic layers were concentrated under reducedpressure and then purified by column chromatography on silica, using 10%EtOH/EtOAc as eluent, to yield2-[3-(2-isopropylpyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol(121 mg, 22%): ¹H NMR (400 MHz, d⁶-DMSO) δ 10.21 (1H, d, J 8.1), 8.76(1H, s), 8.72 (1H, d, J 6.1), 7.88 (1H, d, J 6.1), 7.66 (1H, d, J 8.1),5.57 (1H, s), 3.24 (1H, septet, J 7.7), 1.53 (6H, s), 1.37 (6H, d, J7.7); m/z (ES⁺) 298 (M+H⁺).

EXAMPLES 118 TO 200

[0423] The following compounds were made by methods analogous to thosedescribed above. Example No. Z

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1. A compound of formula I, or a salt or prodrug thereof:

wherein Z represents an optionally substituted five-memberedheteroaromatic ring selected from furan, thiophene, pyrrole, oxazole,thiazole, isoxazole, isothiazole, imidazole, pyrazole, oxadiazole,thiadiazole, triazole and tetrazole; or Z represents an optionallysubstituted six-membered heteroaromatic ring selected from pyridine,pyrazine, pyrimidine and pyridazine; R¹ represents hydrogen,hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl,nitro, —OR^(a), —SR^(a), —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b),—NR^(a)R^(b), —NR^(a)COR^(b), —NR^(a)CO₂R^(b), —COR^(a), —CO₂R^(a),—CONR^(a)R^(b) or —CR^(a)═NOR^(b); and R^(a) and R^(b) independentlyrepresent hydrogen, hydrocarbon or a heterocyclic group.
 2. A compoundas claimed in claim 1 represented by formula IA, and salts and prodrugsthereof:

wherein Z is as defined in claim 1; R¹¹ represents hydrogen, C₁₋₆ alkyl,cyano(C₁₋₆)alkyl, halo(C₁₋₆)alkyl, dihalo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy(C₁₋₆)alkyl, di(C₁₋₆)alkoxy(C₁₋₆)alkyl,C₃₋₇ cycloalkyl, heteroaryl, C₁₋₆ alkyl-heteroaryl,heteroaryl(C₁₋₆)alkyl, halogen, cyano, trifluoromethyl, C₁₋₆ alkoxy,formyl, C₂₋₆ alkylcarbonyl, C₂₋₆ alkoxycarbonyl or —CR⁴═NOR⁵; R⁴represents hydrogen or C₁₋₆ alkyl; and R⁵ represents hydrogen, C₁₋₆alkyl, hydroxy(C₁₋₆)alkyl or di(C₁₋₆)alkylamino(C₁₋₆)alkyl.
 3. Acompound as claimed in claim 2 represented by formula IIA, and salts andprodrugs thereof:

wherein X represents CH and Y represents N; or X represents N and Yrepresents CH or N; R⁶ represents hydrogen, halogen, cyano,trifluoromethyl, C₁₋₆ alkyl, halo(C₁₋₆)alkyl, dihalo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₃₋₇ cycloalkyl, C₃₋₇heterocycloalkyl, benzyl-tetrahydropyridinyl, C₁₋₆ alkoxy,methyltriazolyl(C₁₋₆)alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl, C₂₋₆alkylcarbonyl, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, C₂₋₆alkylcarbonylamino, phenyl, (C₁₋₆)alkyl-phenyl, halophenyl,dihalophenyl, trihalophenyl, (fluoro)(methyl)phenyl, cyanophenyl,(cyano)(fluoro)phenyl, (cyano)(difluoro)phenyl, difluoromethyl-phenyl,trifluoromethyl-phenyl, (methyl)(trifluoromethyl)phenyl,(halo)(trifluoromethyl)phenyl, nitrophenyl, methoxyphenyl,(halo)(methoxy)phenyl, trifluoromethoxy-phenyl,(halo)(trifluoromethoxy)phenyl, methylenedioxy-phenyl,(C₂₋₆)alkylcarbonyl-phenyl, trifluorothio-phenyl,(C₁₋₆)alkylsulphonyl-phenyl, di(C₁₋₆)alkylaminocarbonyl-phenyl,di(C₁₋₆)alkylaminosulphonyl-phenyl, (halo)(morpholinylmethyl)phenyl,(halo)(pyridinyl)phenyl, imidazolyl-phenyl, thiadiazolyl-phenyl,methylthiadiazolyl-phenyl, (halo)(triazolyl)phenyl,methyltetrazolyl-phenyl or optionally substituted heteroaryl, theoptional substituents on the heteroaryl moiety being selected from oxy,halogen, cyano and C₁₋₆ alkyl; and R¹¹ is as defined in claim
 2. 4. Acompound as claimed in claim 3 represented by formula IIB, or apharmaceutically acceptable salt thereof:

wherein X and Y are as defined in claim 3; and R¹¹ is as defined inclaim
 2. 5. A compound as claimed in claim 3 represented by formula IIC,or a pharmaceutically acceptable salt thereof:

wherein R¹⁶ represents hydrogen, fluoro or cyano; X and Y are as definedin claim 3; and R¹¹ is as defined in claim
 2. 6. A compound selectedfrom: 3-(6-bromopyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;2-[6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]-benzonitrile;2-[4-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]-benzonitrile;3-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-(2-chloropyrimidin-4-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-(thiazol-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)nicotinonitrile;3-(pyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-[6-(pyrrolidin-1-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;7-trifluoromethyl-3-(6-trifluoromethylpyridin-2-yl)imidazo[1,2-α]pyrimidine;3-(6-methylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-(6-methoxypyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-(6-cyclopentylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-(5-methylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;7-trifluoromethyl-3-(5-trifluoromethylpyridin-2-yl)imidazo[1,2-α]pyrimidine;2-[4-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyrimidin-2-yl]-benzonitrile;3-[3-(thien-2-yl)-[1,2,4]thiadiazol-5-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-[4-(pyridin-3-yl)thien-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-[5-(pyridin-3-yl)thien-3-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-[4-(pyridin-3-yl)thiazol-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;and salts and prodrugs thereof.
 7. A compound selected from:2-{6-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile;5-fluoro-2-{6-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl}pyridin-2-yl}benzonitrile;3-{6-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}thiophene-2-carbonitrile;4-fluoro-2-{6-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile;3-(6-bromopyridin-2-yl)-7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine;2-{6-[7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile;2-{6-[7-(1-cyano-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyridin-2-yl}benzonitrile;2-[6-(7-tert-butylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]-5-fluorobenzonitrile;4-fluoro-2-[6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl}benzonitrile;3-(2-fluoropyridin-5-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-(2-phenylpyridin-5-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-[2-(4-fluorophenyl)pyridin-5-yl)]-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-[2-(1H-pyrrol-1-yl)pyridin-5-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-(2-chloropyrimidin-4-yl)-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidine;5-fluoro-2-{4-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]-pyrimidin-2-yl}benzonitrile;2-[3-(2-(pyridin-3-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol;2-{4-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}thiophene-3-carbonitrile;5-fluoro-2-{4-[7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}benzonitrile;2-[3-(2-trifluoromethylpyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol;2-[3-(2-(thiazol-2-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol;2-[3-(2-(imidazol-1-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol;2-[3-(2-(pyridin-4-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol2-[3-(2-(furan-2-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol;2-[3-(2-(furan-3-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol;2-{3-[2-(1-oxypyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol;3-[6-(1H-imidazol-1-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-[6-(morpholin-4-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-(6-phenylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,3′-bipyridine;N-[6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]acetamide;N-(tert-butyl)-6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-ylamine;3-[6-(1H-[1,2,4]triazol-1-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-[6-(isothiazol-4-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-(6-isopropoxypyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-(6-ethoxypyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,2′-bipyridine;6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,4′-bipyridine;3-(6-methoxymethylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine;3-[6-(thien-3-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine;7-(1,1-dimethoxyethyl)-3-[2-(pyridinyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine;2-{3-[2-(3-nitrophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol;2-{3-[2-(3-fluorophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol;1-[3-(2-(pyridin-4-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]ethanone;6-[7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-α]pyrimidinyl-3-yl]-2,3′-bipyridine;2-[6-(7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]benzonitrile;6′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,2′-bipyridinyl-3-carbonitrile;6′-[7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]-2,2′-bipyridinyl-3-carbonitrile;the compounds whose structures are depicted in the accompanying Tablesas Examples 68 to 109; and salts and prodrugs thereof.
 8. A compoundselected from:2-{3-[2-(2,4-difluorophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol;2-{3-[2-(3,4-difluorophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol;2-{3-[2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl)propan-2-ol;2-{3-[2-(1,1-difluoroethyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol;1-{4-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}ethanone;2-{3-[2-(1-hydroxy-1-methylethyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol;2-{3-[2-(1-fluoro-1-methylethyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidin-7-yl}propan-2-ol;2-[3-(2-isopropylpyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol;the compounds whose structures are depicted in the accompanying Tablesas Examples 118 to 200; and salts and prodrugs thereof.
 9. Apharmaceutical composition comprising a compound of formula I as definedin claim 1, or a pharmaceutically acceptable salt thereof or a prodrugthereof, in association with a pharmaceutically acceptable carrier. 10.The use of a compound of formula I as defined in claim 1, or apharmaceutically acceptable salt thereof or a prodrug thereof, for themanufacture of a medicament for the treatment and/or prevention ofadverse neurological conditions.
 11. A process for the preparation of acompound as claimed in claim 1, which comprises: (A) reacting a compoundof formula III with a compound of formula IV:

L¹-Z   (IV) wherein Z and R¹ are as defined in claim 1, L¹ represents asuitable leaving group, and M¹ represents a boronic acid moiety —B(OH)₂or a cyclic ester thereof formed with an organic diol, or M¹ represents—Sn(Alk)₃ in which Alk represents C₁₋₆ alkyl; in the presence of atransition metal catalyst; or (B) reacting a compound of formula V witha compound of formula VI:

wherein Z and R¹ are as defined in claim 1, and L¹ and M¹ are as definedabove; in the presence of a transition metal catalyst; or (C) reacting acompound of formula VII with a compound of formula VIII:

wherein R¹ is as defined in claim 1, R⁷ represents any allowablesubstituent on the group Z, and Hal represents a halogen atom; or (D)reacting a compound of formula XV with a compound of formula XVI:R^(1a)-M¹   (XV)

wherein Z is as defined in claim 1, M¹ is as defined above, R^(1a)represents an aryl or heteroaryl moiety, and L² represents a suitableleaving group; in the presence of a transition metal catalyst; or (E)reacting a compound of formula IV as defined above with a compound offormula IX:

wherein R¹ is as defined in claim 1; in the presence of a transitionmetal catalyst; and (F) where appropriate, converting a compound offormula I initially obtained into a further compound of formula I bystandard methods.
 12. A method for the treatment and/or prevention ofadverse neurological conditions which comprises administering to apatient in need of such treatment an effective amount of a compound offormula I as defined in claim 1, or a pharmaceutically acceptable saltthereof or a prodrug thereof.